HRP20020373A2 - Novel cyclopropanes as cgrp antagonists, medicaments containing said compounds and method for the production thereof - Google Patents
Novel cyclopropanes as cgrp antagonists, medicaments containing said compounds and method for the production thereof Download PDFInfo
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- HRP20020373A2 HRP20020373A2 HR20020373A HRP20020373A HRP20020373A2 HR P20020373 A2 HRP20020373 A2 HR P20020373A2 HR 20020373 A HR20020373 A HR 20020373A HR P20020373 A HRP20020373 A HR P20020373A HR P20020373 A2 HRP20020373 A2 HR P20020373A2
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- carbonyl
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- general formula
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 77
- 238000000034 method Methods 0.000 title claims abstract description 21
- 150000001942 cyclopropanes Chemical class 0.000 title claims description 4
- 229940127597 CGRP antagonist Drugs 0.000 title description 2
- 238000004519 manufacturing process Methods 0.000 title description 2
- 239000003814 drug Substances 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- -1 biphenylyl Chemical group 0.000 claims description 140
- 239000000203 mixture Substances 0.000 claims description 53
- 238000002360 preparation method Methods 0.000 claims description 31
- 125000001424 substituent group Chemical group 0.000 claims description 31
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 29
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 125000000623 heterocyclic group Chemical group 0.000 claims description 28
- 229910052757 nitrogen Inorganic materials 0.000 claims description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 24
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 21
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 239000000460 chlorine Substances 0.000 claims description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- 229910052801 chlorine Inorganic materials 0.000 claims description 18
- 125000001246 bromo group Chemical group Br* 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 16
- 239000011737 fluorine Substances 0.000 claims description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 229910021529 ammonia Inorganic materials 0.000 claims description 14
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 13
- 125000004076 pyridyl group Chemical group 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 125000001153 fluoro group Chemical group F* 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 8
- 125000001589 carboacyl group Chemical group 0.000 claims description 8
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 8
- 125000005331 diazinyl group Chemical group N1=NC(=CC=C1)* 0.000 claims description 8
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 8
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 8
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 8
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 8
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 8
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 6
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 125000002837 carbocyclic group Chemical group 0.000 claims description 6
- 150000001721 carbon Chemical group 0.000 claims description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 6
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- 150000007522 mineralic acids Chemical class 0.000 claims description 6
- 150000007524 organic acids Chemical class 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 6
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 6
- 238000007127 saponification reaction Methods 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 229940055764 triaz Drugs 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 4
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 4
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 4
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004949 alkyl amino carbonyl amino group Chemical group 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000006598 aminocarbonylamino group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000005605 benzo group Chemical group 0.000 claims description 4
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000004984 dialkylaminoalkoxy group Chemical group 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 4
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 238000011282 treatment Methods 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 4
- WRIOMYHORIZPQI-QZTJIDSGSA-N 2-[[3-[1-[(1r,2r)-2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]piperidin-4-yl]-2-oxo-1,4-dihydroquinazolin-6-yl]oxy]acetic acid Chemical compound C1=C(Br)C(N)=C(Br)C=C1C(=O)[C@H]1[C@H](C(=O)N2CCC(CC2)N2C(NC3=CC=C(OCC(O)=O)C=C3C2)=O)C1 WRIOMYHORIZPQI-QZTJIDSGSA-N 0.000 claims description 3
- 230000001154 acute effect Effects 0.000 claims description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 3
- 230000017531 blood circulation Effects 0.000 claims description 3
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 208000027866 inflammatory disease Diseases 0.000 claims description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 3
- POOJFXSMPZMEBU-RTBURBONSA-N methyl 2-[[3-[1-[(1r,2r)-2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]piperidin-4-yl]-2-oxo-1,4-dihydroquinazolin-6-yl]oxy]acetate Chemical compound O=C([C@@H]1C[C@H]1C(=O)N1CCC(CC1)N1C(=O)NC2=CC=C(C=C2C1)OCC(=O)OC)C1=CC(Br)=C(N)C(Br)=C1 POOJFXSMPZMEBU-RTBURBONSA-N 0.000 claims description 3
- 235000005985 organic acids Nutrition 0.000 claims description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 3
- 230000024883 vasodilation Effects 0.000 claims description 3
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical compound CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 claims description 2
- OVEBHCCJIWQLFX-SKLUMECTSA-N 1-[1-[(1r,2r)-2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]piperidin-4-yl]-5-phenyl-1,2,4-triazolidin-3-one Chemical compound C1=C(Br)C(N)=C(Br)C=C1C(=O)[C@H]1[C@H](C(=O)N2CCC(CC2)N2C(NC(=O)N2)C=2C=CC=CC=2)C1 OVEBHCCJIWQLFX-SKLUMECTSA-N 0.000 claims description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000000586 2-(4-morpholinyl)ethoxy group Chemical group [H]C([H])(O*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- KUKIMOYIGBFOHW-IAGOWNOFSA-N 3-[1-[(1r,2r)-2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]piperidin-4-yl]-1,4-dihydroquinazolin-2-one Chemical compound C1=C(Br)C(N)=C(Br)C=C1C(=O)[C@H]1[C@H](C(=O)N2CCC(CC2)N2C(NC3=CC=CC=C3C2)=O)C1 KUKIMOYIGBFOHW-IAGOWNOFSA-N 0.000 claims description 2
- JYOGPDQDXPDNHR-QZTJIDSGSA-N 3-[1-[(1r,2r)-2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]piperidin-4-yl]-5-(3-chlorophenyl)-1h-imidazol-2-one Chemical compound C1=C(Br)C(N)=C(Br)C=C1C(=O)[C@H]1[C@H](C(=O)N2CCC(CC2)N2C(NC(=C2)C=2C=C(Cl)C=CC=2)=O)C1 JYOGPDQDXPDNHR-QZTJIDSGSA-N 0.000 claims description 2
- HGPRJNNGQCPFDR-RTBURBONSA-N 3-[1-[(1r,2r)-2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]piperidin-4-yl]-5-(3-methoxyphenyl)-1h-imidazol-2-one Chemical compound COC1=CC=CC(C=2NC(=O)N(C3CCN(CC3)C(=O)[C@H]3[C@@H](C3)C(=O)C=3C=C(Br)C(N)=C(Br)C=3)C=2)=C1 HGPRJNNGQCPFDR-RTBURBONSA-N 0.000 claims description 2
- FVBTUAQLPAVBGJ-FGZHOGPDSA-N 3-[1-[(1r,2r)-2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]piperidin-4-yl]-6-[3-(dimethylamino)propoxy]-1,4-dihydroquinazolin-2-one Chemical compound O=C([C@@H]1C[C@H]1C(=O)N1CCC(CC1)N1C(=O)NC2=CC=C(C=C2C1)OCCCN(C)C)C1=CC(Br)=C(N)C(Br)=C1 FVBTUAQLPAVBGJ-FGZHOGPDSA-N 0.000 claims description 2
- QJILSEPJTKVBDW-IAGOWNOFSA-N 3-[1-[(1r,2r)-2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]piperidin-4-yl]-6-hydroxy-1,4-dihydroquinazolin-2-one Chemical compound C1=C(Br)C(N)=C(Br)C=C1C(=O)[C@H]1[C@H](C(=O)N2CCC(CC2)N2C(NC3=CC=C(O)C=C3C2)=O)C1 QJILSEPJTKVBDW-IAGOWNOFSA-N 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
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- 208000033830 Hot Flashes Diseases 0.000 claims description 2
- 206010060800 Hot flush Diseases 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
- 206010047141 Vasodilatation Diseases 0.000 claims description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 150000003973 alkyl amines Chemical class 0.000 claims description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
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- 201000010105 allergic rhinitis Diseases 0.000 claims description 2
- 208000006673 asthma Diseases 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 2
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
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- 231100000869 headache Toxicity 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 2
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 2
- 229960005181 morphine Drugs 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims description 2
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- 239000000969 carrier Substances 0.000 claims 2
- NUBNSKOIGYPWDD-QZTJIDSGSA-N 3-[1-[(1r,2r)-2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]piperidin-4-yl]-5-(3-hydroxyphenyl)-1h-imidazol-2-one Chemical compound C1=C(Br)C(N)=C(Br)C=C1C(=O)[C@H]1[C@H](C(=O)N2CCC(CC2)N2C(NC(=C2)C=2C=C(O)C=CC=2)=O)C1 NUBNSKOIGYPWDD-QZTJIDSGSA-N 0.000 claims 1
- RLJLQNLYLWGOES-QZTJIDSGSA-N 3-[1-[(1r,2r)-2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]piperidin-4-yl]-5-phenyl-1h-imidazol-2-one Chemical compound C1=C(Br)C(N)=C(Br)C=C1C(=O)[C@H]1[C@H](C(=O)N2CCC(CC2)N2C(NC(=C2)C=2C=CC=CC=2)=O)C1 RLJLQNLYLWGOES-QZTJIDSGSA-N 0.000 claims 1
- UTATXYLZLKRHCP-WOJBJXKFSA-N 3-[1-[(1r,2r)-2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]piperidin-4-yl]-6-(1,3-dioxolan-2-ylmethoxy)-1,4-dihydroquinazolin-2-one Chemical compound C1=C(Br)C(N)=C(Br)C=C1C(=O)[C@H]1[C@H](C(=O)N2CCC(CC2)N2C(NC3=CC=C(OCC4OCCO4)C=C3C2)=O)C1 UTATXYLZLKRHCP-WOJBJXKFSA-N 0.000 claims 1
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- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 description 1
- 229960000482 pethidine Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229960003910 promethazine Drugs 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960000425 rizatriptan Drugs 0.000 description 1
- TXHZXHICDBAVJW-UHFFFAOYSA-N rizatriptan Chemical compound C=1[C]2C(CCN(C)C)=CN=C2C=CC=1CN1C=NC=N1 TXHZXHICDBAVJW-UHFFFAOYSA-N 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229940086766 sodium chloride 180 mg Drugs 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- CWXOAQXKPAENDI-UHFFFAOYSA-N sodium methylsulfinylmethylide Chemical compound [Na+].CS([CH2-])=O CWXOAQXKPAENDI-UHFFFAOYSA-N 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003760 tallow Substances 0.000 description 1
- RVLBWBWZOLQRMM-UHFFFAOYSA-N tert-butyl 4-(6-bromo-2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1N1C(=O)NC2=CC=C(Br)C=C2C1 RVLBWBWZOLQRMM-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 150000005622 tetraalkylammonium hydroxides Chemical class 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 238000005533 tritiation Methods 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 229940102566 valproate Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- WEKISHNHYNINFX-UHFFFAOYSA-N zinc;iodomethane Chemical compound [Zn+2].I[CH2-].I[CH2-] WEKISHNHYNINFX-UHFFFAOYSA-N 0.000 description 1
- ULSDMUVEXKOYBU-ZDUSSCGKSA-N zolmitriptan Chemical compound C1=C2C(CCN(C)C)=CNC2=CC=C1C[C@H]1COC(=O)N1 ULSDMUVEXKOYBU-ZDUSSCGKSA-N 0.000 description 1
- 229960001360 zolmitriptan Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
Description
Predloženi izum odnosi se na nove ciklopropane opće formule The proposed invention relates to new cyclopropanes of the general formula
[image] [image]
na njihove tautomere, diastereomere, enantiomere, njihove smjese i njihove soli, posebno njihove fiziološki prihvatljive soli s anorganskim ili organskim kiselinama ili bazama, farmaceutske pripravke' koji sadrže te spojeve, njihovu upotrebu i postupke za njihovu pripravu. U gornjoj općoj formuli (I) to their tautomers, diastereomers, enantiomers, their mixtures and their salts, especially their physiologically acceptable salts with inorganic or organic acids or bases, pharmaceutical preparations containing these compounds, their use and procedures for their preparation. In the above general formula (I)
R predstavlja zasićenu, mono- ili di-nezasićenu 5- do 7-članu aza, diaza, triaza, oksaza, tiaza, tiadiaza ili S,S-dioksido-tiadiaza heterocikličku skupinu, R represents a saturated, mono- or di-unsaturated 5- to 7-membered aza, diaza, triaz, oxaz, thiaz, thiadiaz or S,S-dioxido-thiadiaz heterocyclic group,
pri čemu gore spomenute heteroctkličke skupine su povezane preko ugljikovog ili dušikovog atoma i whereby the above-mentioned heterocyclic groups are connected through a carbon or nitrogen atom and
mogu sadržavati jednu ili dvije karbonilne skupine susjedne do dušikovog atoma, may contain one or two carbonyl groups adjacent to the nitrogen atom,
mogu biti supstituirane s alkilnim skupinama na jednom dušikovom atomu, may be substituted with alkyl groups on one nitrogen atom,
mogu biti supstituirane na jednom ili dva ugljikova atoma sa supstituentom iz niza koji čine alkilna skupina ravnog ili razgranatog lanca, fenil, feni1-metil, naftil, bifenilil, piridinil, diazinil, furil, tienil, pirolil, 1,3-oksazolil, 1,3-tiazolil, izoksazolil, pirazolil, 1-metilpirazolil, imidazolil ili 1-metil-imidazolilna skupina, pri čemu supstituenti mogu biti jednaki ili različiti, can be substituted on one or two carbon atoms with a substituent from the series that form a straight or branched chain alkyl group, phenyl, phenyl-methyl, naphthyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1, 3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or 1-methyl-imidazolyl group, wherein the substituents can be the same or different,
i pri čemu olefinska dvostruka veza jedne od gore spomenutih nezasićenih heterocikličkih skupina može biti kondenzirana sa skupinom iz niza koji čine benzen, piridin, diazin, 1,3-oksazol, tiofen, furan, tiazol, pirol, N-metil-pirol, kinolin, imidazol ili N-metil-imidazolni prsten, and wherein the olefinic double bond of one of the aforementioned unsaturated heterocyclic groups can be condensed with a group from the series consisting of benzene, pyridine, diazine, 1,3-oxazole, thiophene, furan, thiazole, pyrrole, N-methyl-pyrrole, quinoline, imidazole or N-methyl-imidazole ring,
dok fenil, piridinil, diazinil, furil, tienil, pirolil, 1,3-oksazolil, 1,3-tiazolil, izoksazolil, pirazolil, 1-metilpirazolil, imidazolil ili 1-metil-imidazolilna skupina sadržana u R i benzo-, tieno-, pirido-i diazino-kondenzirane heterocikličke skupine u ugljikovom kosturu mogu dodatno biti mono-, di- ili trisupstituirane sa supstituentom iz niza koji čine atomi fluora, klora ili broma, alkil, dialkilaminoalkoksi, nitro, alkiltio, alkil-sulfinil, alkilsulfonil, alkilsuLfonilamino, fenil, tri-fluormetil, alkoksikarbonil, alkcisikarbonilalkil, alkoksi-karbonilalkoksi, hidroksikarbonilalkoksi, karboksi, karboksialkil, dialkilaminoalkil, hidroksi, amino, acetil-amino, propionilamino, aminokarhonil, alkilaminokarbonil, dialkilaminokarbonil, [N-alkil-N-.dialkilaminoalkil)amino]-karbonil, [(hidroksikarronilalkil) amino] karbonil, [(alkoksi-karbonilalkil)amino]karbonil, (4-morfolinil)-karbonil, (1-pirolidinil)karbonil, -(1-piperidinil)karbonil, (heksahidro-1-azepinil)karbonil, (4-metil-1-piperazinil)-karbonil, metilendioksi, aminokarbonilamino, aminokarbonil-aminoalkil, alkilaminokarbonilamino, alkanoil, cijano, tri-fluormetoksi, trifluormetiltio, trifluormetilsulfinil, tri-fluormetilsulfonil ili cikloalkilne skupine s 3 do 8 ugljikovih atoma, while phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or 1-methyl-imidazolyl group contained in R and benzo-, thieno- , pyrido- and diazino-condensed heterocyclic groups in the carbon skeleton can additionally be mono-, di- or trisubstituted with a substituent from the series consisting of fluorine, chlorine or bromine atoms, alkyl, dialkylaminoalkoxy, nitro, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino . ]-carbonyl, [(hydroxycarronylalkyl)amino]carbonyl, [(Alkoxy-carbonylalkyl)amino]carbonyl, (4-morpholinyl)-carbonyl, (1-pyrrolidinyl)carbonyl, -(1-piperidinyl)carbonyl, (hexahydro-1- azepinyl)carbonyl, (4-methyl-1-pipe erazinyl)-carbonyl, methylenedioxy, aminocarbonylamino, aminocarbonyl-aminoalkyl, alkylaminocarbonylamino, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl, trifluoromethylsulfonyl or cycloalkyl groups with 3 to 8 carbon atoms,
4- do 8-člane alkilenamino skupine pri čemu metilenska skupina u položaju 3, 4 ili 5 može biti zamijenjena s kisikovim atomom ili metilimino skupinom, 4- to 8-membered alkyleneamino groups, whereby the methylene group in position 3, 4 or 5 can be replaced with an oxygen atom or a methylimino group,
alkoksi skupine koje mogu biti supstituirane u položaju ω s 5- do 7-članom heteroalicikličkom skupinom pri čemu je heteroaliciklička skupina povezana preko ugljikovog ili dušikovog atoma i sadrži jedan ili dva heteroatoma koji nisu izravno međusobno povezani i odabrani su između kisika i dušika, Alkoxy groups that can be substituted in the ω position with a 5- to 7-membered heteroalicyclic group, wherein the heteroalicyclic group is connected via a carbon or nitrogen atom and contains one or two heteroatoms that are not directly connected to each other and are selected from oxygen and nitrogen,
pri čemu je isključena višestruka supstitucija sa cikličkim skupinama ili s onim skupinama koje sadrže karbocikličku ili heterocikličku skupinu i pri čemu supstituenti mogu biti jednaki ili različiti, whereby multiple substitution with cyclic groups or with those groups containing a carbocyclic or heterocyclic group is excluded and wherein the substituents may be the same or different,
i R1 predstavlja fenil, 1-naftil, 2-naftil, 1,2,3,4-tetrahidro-1-naftil, 1H-indol-3-il, 1-metil-1H-indol-3-il, 1-formil-1H-indol-3-il, 4-imidazolil, 1-metil-4-imidazolil, 2-tienil, 3-tienil, tiazolil, 1H-indazol-3-il, 1-metil-1H-indazol-3-il, benzo[b]fur-3-il, benzo[b]tien-3-il, piridinil, kinolinil ili izokinolinilnu skupinu, and R1 represents phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl -1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, 1H-indazol-3-yl, 1-methyl-1H-indazol-3-yl , benzo[b]fur-3-yl, benzo[b]thien-3-yl, pyridinyl, quinolinyl or isoquinolinyl group,
dok gore spomenute aromatske i heteroaromatske skupine mogu dodatno biti mono-, di- ili trisupstituirane u ugljikovom kosturu s atomima fluora, klora ili broma, s razgranatim ili nerazgranatim alkilnim skupinama, sa cikloalkilnim skupinama s 3 do 8 ugljikovim atoma, sa supstituentima iz niza koji čine fenilalkil, alkenil, alkoksi, fenil, fenilalkoksi, trifluormetil, alkoksi-karbonilalkil, karboksialkil, alkoksikarbonil, karboksi, dialkilaminoalkil, dialkilaminoalkoksi, nitro, hidroksi, amino, acetilamino, propionilamino, metilsulfoniloksi, aminokarbonil, alkilaminokarbonil, dialkilaminokarbonil, alkanoil, cijano, tetrazolil, fenil, piridinil, tiazolil, furil, trifluormetoksi, trifluormetiltio, trifluormetil-sulfinil ili trifluormetilsulfonilna skupina, while the above-mentioned aromatic and heteroaromatic groups can additionally be mono-, di- or trisubstituted in the carbon skeleton with fluorine, chlorine or bromine atoms, with branched or unbranched alkyl groups, with cycloalkyl groups with 3 to 8 carbon atoms, with substituents from the series that consist of phenylalkyl, alkenyl, alkoxy, phenyl, phenylalkyloxy, trifluoromethyl, alkoxy-carbonylalkyl, carboxyalkyl, alkoxycarbonyl, carboxy, dialkylaminoalkyl, dialkylaminoalkyl, nitro, hydroxy, amino, acetylamino, propionylamino, methylsulfonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, tetrazolyl , phenyl, pyridinyl, thiazolyl, furyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl group,
i supstituenti mogu biti jednaki ili različiti, and the substituents can be the same or different,
dok hidroksi, amino, indolil i imidazolilne skupine sadržane u gore spomenutim skupinama mogu biti supstituirane sa zaštitnim skupinama koje su poznate iz kemije peptida, prednosno s acetilnom, benziloksi-karbonilnom ili terc-butiloksikarbonilnom skupinom, i while the hydroxy, amino, indolyl and imidazolyl groups contained in the above-mentioned groups can be substituted with protective groups known from peptide chemistry, preferably with an acetyl, benzyloxy-carbonyl or tert-butyloxycarbonyl group, and
sve gore spomenute alkilno i alkoksi skupine i alkilne ili alkilenske skupine prisutne u drugim navedenim skupinama mogu sadržavati 1 do 5 ugljikovih atoma, ako nije navedeno drugačije. all the aforementioned alkyl and alkoxy groups and the alkyl or alkylene groups present in the other mentioned groups may contain 1 to 5 carbon atoms, unless otherwise stated.
Pod zaštitnim skupinama, spomenutim u prethodnim definicijama, misli se na zaštitne skupine koje su poznate iz kemije peptida, posebno By protecting groups, mentioned in the previous definitions, we mean protecting groups that are known from peptide chemistry, especially
fenilalkoksikarbonilnu skupinu s 1 do 3 ugljikova atoma u alkoksi skupini prema potrebi supstituiranoj u fenilnoj jezgri s halogenim atomom, s nitro ili fenilnom skupinom, s jednom ili dvije metoksi skupine, a phenylalkyloxycarbonyl group with 1 to 3 carbon atoms in the alkoxy group optionally substituted in the phenyl nucleus with a halogen atom, with a nitro or phenyl group, with one or two methoxy groups,
na primjer benziloksikarbonil, 2-nitro-benziloksi-karbonil, 4-nitro-benziloksikarbonil, 4-metoksi-benziloksi-karbonil, 2-klor-benziloksikarbonil, 3-klor-benziloksi-karbonil, 4-klor-benziloksikarbonil, 4-bifenilil-α,α-di-metil-benziloksikarbonil ili 3,5-dimetoksi-α,α-dimetil-benziloksikarbonilna skupina, for example benzyloxycarbonyl, 2-nitro-benzyloxy-carbonyl, 4-nitro-benzyloxycarbonyl, 4-methoxy-benzyloxy-carbonyl, 2-chloro-benzyloxycarbonyl, 3-chloro-benzyloxy-carbonyl, 4-chloro-benzyloxycarbonyl, 4-biphenylyl- α,α-dimethyl-benzyloxycarbonyl or 3,5-dimethoxy-α,α-dimethyl-benzyloxycarbonyl group,
alkoksikarbonilnu skupinu koja ima ukupno 1 do 5 ugljikovih atoma u alkilnoj skupini, an alkoxycarbonyl group that has a total of 1 to 5 carbon atoms in the alkyl group,
na primjer metoksikarbonil, etoksikarbonil, n-propoksikarbonil, izopropoksikarbonil, n-butoksikarbonil, 1-metilpropoksikarbonil, 2-metilpropoksi-karbonil ili terc-butiloksikarbonilna skupina, for example methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, 1-methylpropoxycarbonyl, 2-methylpropoxycarbonyl or tert-butyloxycarbonyl group,
aliloksikarbonil, 2,2,2-triklor-(1,1-dimetiletoksi)-karbonil ili 9-fluorenilmetoksikarbonilnu skupinu ili formilnu, acetilnu ili triflucracetilnu skupinu. an allyloxycarbonyl, 2,2,2-trichloro-(1,1-dimethylethoxy)carbonyl or 9-fluorenylmethoxycarbonyl group or a formyl, acetyl or triflucraacetyl group.
Predloženi izum također uključuje pojedinačne diastereomerne parove antipoda opće formule (I), sjedinjene enantiomere i smjese diastereomera i enantiomera koji spadaju pod opću formulu (I). The proposed invention also includes individual diastereomeric pairs of antipodes of general formula (I), combined enantiomers and mixtures of diastereomers and enantiomers falling under general formula (I).
Posebno prednosni su racemati i enantiomeri koji spadaju pod opću formulu (I) i imaju trans konfiguraciju u odnosu prema ciklopropanskom prstenu. Particularly preferred are racemates and enantiomers that fall under the general formula (I) and have a trans configuration in relation to the cyclopropane ring.
Spojevi opće formule (I) imaju dragocjena farmakološka svojstva, koja se temelje na njihovim selektivnim CGRP-antagonističkim svojstvima. Izum se, nadalje, odnosi na farmaceutske pripravke koji sadrže te spojeve, na njihovu upotrebu i na njihovu pripravu. The compounds of general formula (I) have valuable pharmacological properties, which are based on their selective CGRP-antagonistic properties. The invention also relates to pharmaceutical preparations containing these compounds, their use and their preparation.
Prednosni spojevi gornje opće formule I su oni u kojima Preferred compounds of the above general formula I are those in which
R predstavlja mono- ili di-nezasićenu 5- do 7-članu aza, diaza, triaza ili tiaza heterocikličku skupinu, R represents a mono- or di-unsaturated 5- to 7-membered aza, diaza, triaz or thiaz heterocyclic group,
dok gore spomenute heterocikličke skupine su povezane preko ugljikovog ili dušikovog atoma i while the above-mentioned heterocyclic groups are linked through a carbon or nitrogen atom and
mogu sadržavati jednu ili dvije karbonilne skupine susjedne do dušikovog atoma, may contain one or two carbonyl groups adjacent to the nitrogen atom,
mogu biti supstituirane na ugljikovom atomu sa "supstituentom iz niza koji čine fenil, piridinil, diazinil,tienil, pirolil, 1,3-tiazolil, izoksazolil, pirazolil ili 1-metilpirazolilna skupina, can be substituted on the carbon atom with a "substituent from the series consisting of phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl or 1-methylpyrazolyl group,
i pri čemu olefinska dvostruka veza jedne od gore spomenutih nezasićenih heterocikličkih skupina može biti kondenzirana na benzenski, piridinski, diazinski ili_ kinolinski prsten, and wherein the olefinic double bond of one of the aforementioned unsaturated heterocyclic groups may be fused to a benzene, pyridine, diazine or quinoline ring,
dok fenil, piridinil, diazinil, tienil, pirolil, 1,3-tiazolil, izoksazolil, pirazolil ili 1-metilpirazolilna skupina sadržana u R i benzo-, pirido- i diazino-kondenzirane heterocikličke skupine u ugljikovom kosturu mogu dodatno biti mono-, di- ili trisupstituirane s atomima fluora, klora ili broma, sa supstituentom iz niza koji čine alkil, dialkilaminoalkoksi, nitro, trifluormetil, alkoksikarbonil, alkoksikarbonilalkil, alkoksikarbonilalkoksi, hidroksikarbonilalkoksi, karboksi, karboksialkil, dialkil-aminoalkil, hidroksi, amino, acetilamino, propionilamino, aminokarbonil, alkilaminokarbonil, dialkilaminokarbonil, [N-alkil-N-(dialkilaminoalkil)amino]karbonil, [(hidroksi-karbonilalkil)amino]karbonil, [(alkoksikarbonilalkil)-amino]karbonil, aminokarbonilamino, aminokarbonilamino-alkil, alkilaminokarbonilamino, alkanoil ili trifluor-metoksi skupina, while the phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl or 1-methylpyrazolyl group contained in R and the benzo-, pyrido- and diazino-fused heterocyclic groups in the carbon skeleton can additionally be mono-, di - or tri-substituted with fluorine, chlorine or bromine atoms, with a substituent from the series consisting of alkyl, dialkylaminoalkyl, nitro, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkyl, hydroxycarbonylalkyl, carboxy, carboxyalkyl, dialkyl-aminoalkyl, hydroxy, amino, acetylamino, propionylamino, aminocarbonyl , alkylaminocarbonyl, dialkylaminocarbonyl, [N-alkyl-N-(dialkylaminoalkyl)amino]carbonyl, [(hydroxy-carbonylalkyl)amino]carbonyl, [(alkoxycarbonylalkyl)-amino]carbonyl, aminocarbonylamino, aminocarbonylamino-alkyl, alkylaminocarbonylamino, alkanoyl or trifluoro- methoxy group,
s 5- do 7-članim alkilenimino skupinama, pri čemu metilenska skupina u položaju 3, 4 ili 5 može biti zamijenjena s kisikovim atomom ili s metilamino skupinom, with 5- to 7-membered alkyleneimino groups, whereby the methylene group in position 3, 4 or 5 can be replaced with an oxygen atom or with a methylamino group,
s alkoksi skupinama koje mogu biti supstituirane u položaju o s 5- do 7-članom heteroalicikličkom skupinom, pri čemu je heteroaliciklička skupina povezana preko ugljikovog ili dušikovog atoma i sadrži jedan ili dva heteroatoma koji nisu međusobno izravno povezani i odabrani su između kisika i dušika, with alkoxy groups that can be substituted in the o position with a 5- to 7-membered heteroalicyclic group, wherein the heteroalicyclic group is connected via a carbon or nitrogen atom and contains one or two heteroatoms that are not directly connected to each other and are selected from oxygen and nitrogen,
pri čemu je isključena višestruka supstitucija sa cikličkim skupinama ili onim skupinama ko~je sadrže karbocikličku ili heterocikličku skupinu i pri čemu supstittienti mogu biti jednaki ili različiti, whereby multiple substitution with cyclic groups or those groups containing a carbocyclic or heterocyclic group is excluded and wherein the substituents may be the same or different,
i R1 predstavlja fenil, 1-naftil ili 2-naftilnu skupinu, and R1 represents a phenyl, 1-naphthyl or 2-naphthyl group,
dok gore spomenute aromatske skupine mogu biti mono-, di- ili trisupstituirane s atomima fluora, klora ili broma, s razgranatim ili nerazgranatim alkilnim skupinama, s alkoksi, trifluormetilnom, nitro, hidroksi, amino ili acetilamino skupinom i supstituenti mogu biti jednaki ili različiti, while the above-mentioned aromatic groups can be mono-, di- or tri-substituted with fluorine, chlorine or bromine atoms, with branched or unbranched alkyl groups, with an alkoxy, trifluoromethyl, nitro, hydroxy, amino or acetylamino group and the substituents can be the same or different,
i pri čemu sve gore spomenute alkilne i alkoksi skupine i alkilne ili alkilenske skupine prisutne u drugim spomenutim skupinama mogu sadržavati 1 do 4 ugljikova atoma, ako nije navedeno drugačije, njihovi tautomeri, diastereomeri, enantiomeri i njihove soli. and wherein all the aforementioned alkyl and alkoxy groups and the alkyl or alkylene groups present in the other mentioned groups may contain 1 to 4 carbon atoms, unless otherwise stated, their tautomers, diastereomers, enantiomers and their salts.
Posebno prednosni spojevi gornje opće formule I su oni u kojima R predstavlja mono-nezasićenu 5- do 7-članu diaza ili triaza heterocikličku skupinu, dok gore spomenute heterocikličke skupine su povezane preko dušikovog atoma, i mogu sadržavati karbonilnu skupinu susjednu do dušikovog atoma, i mogu biti supstituirane na ugljikovom atomu s fenilnom skupinom ili olefinska dvostruka veza jedne od gore spomenutih nezasićenih heterocikličkih skupina može biti kondenzirana s benzenskim, piridinskim ili kinolinskim prstenom, Particularly preferred compounds of the above general formula I are those in which R represents a mono-unsaturated 5- to 7-membered diaza or triaz heterocyclic group, while the above-mentioned heterocyclic groups are connected via a nitrogen atom, and may contain a carbonyl group adjacent to the nitrogen atom, and may be substituted on the carbon atom with a phenyl group or the olefinic double bond of one of the aforementioned unsaturated heterocyclic groups may be condensed with a benzene, pyridine or quinoline ring,
i fenilne skupine sadržane u R kao i benzo- i pirido-kondenzirane heterocikličke skupine u ugljikovom kosturu mogu dodatno biti mono-, di- ili trisupstituirane s atomima fluora, klora ili broma, sa skupinom iz niza koji čine alkil, dialkilaminoalkoksi, nitro, trifluormetil, alkoksi-karboniF, alkoksikarbonilalkoksi, hidroksikarbonilalkoksi, karboksi, hidroksi, aminokarbonil, alkilaminokarbonil, dialkilaminokarbonil, [N-alkil-N-(dialkilaminoalkil)-amino]karbonil, [(hidroksikarbonilalkil)amino]karbonil, [(alkoksikarbonilalkil)amino]karbonil, alkanoil ili tri-fluormetoksi skupinama, and phenyl groups contained in R as well as benzo- and pyrido-condensed heterocyclic groups in the carbon skeleton can additionally be mono-, di- or tri-substituted with fluorine, chlorine or bromine atoms, with a group from the series consisting of alkyl, dialkylaminoalkoxy, nitro, trifluoromethyl . alkanoyl or tri-fluoromethoxy groups,
s 5- do 7-članim alkilenimino skupinama, pri čemu metilenska skupina položaju u 3 ili 4 može biti zamijenjena s kisikovim atomom ili s metilimino skupinom, kao što su na primjer 1-pirolidinil, 1-piperidinil, 4-metil-1-piperazinil, 4-metil-1,4-diazaciklohept-1-il ili 4-morfolinilna skupina, with 5- to 7-membered alkyleneimino groups, whereby the methylene group in position 3 or 4 can be replaced with an oxygen atom or with a methylimino group, such as for example 1-pyrrolidinyl, 1-piperidinyl, 4-methyl-1-piperazinyl , 4-methyl-1,4-diazacyclohept-1-yl or 4-morpholinyl group,
s alkoksi skupinama koje mogu biti supstituirane u položaju ω s 5- ili 6-članom heteroalicikličkom skupinom, pri čemu heteroaliciklička skupina je povezana preko ugljikovog atoma i sadrži kisikov atom u svakom od položaja 2 i 2' ili je povezana preko ugljikovog ili dušikovog atoma i sadrži jedan ili dva dušikova atoma koji nisu izravno međusobno povezani ili kisikov i dušikov atom koji su međusobno odvojeni s najmanje jednom metilenskom skupinom, na primjer metoksi, etoksi, propoksi, 2,5-dioksaciklo-pentilmetoksi, 2,6-dioksacikloheksilmetoksi, 2-(1-pirolidinil)etoksi, 2-(1-piperidinil)etoksi, 2-(4-metil-1-piperazinil)etoksi ili 2-(4-morfolinil)etoksi skupinom, with alkoxy groups that can be substituted in the ω position with a 5- or 6-membered heteroalicyclic group, wherein the heteroalicyclic group is connected via a carbon atom and contains an oxygen atom in each of the 2 and 2' positions or is connected via a carbon or nitrogen atom and contains one or two nitrogen atoms that are not directly connected to each other or an oxygen and a nitrogen atom that are separated from each other by at least one methylene group, for example methoxy, ethoxy, propoxy, 2,5-dioxacyclo-pentylmethoxy, 2,6-dioxacyclohexylmethoxy, 2- (1-pyrrolidinyl)ethoxy, 2-(1-piperidinyl)ethoxy, 2-(4-methyl-1-piperazinyl)ethoxy or 2-(4-morpholinyl)ethoxy group,
pri čemu su isključene višestruke supstitucije sa cikličkim skupinama ili s onim skupinama koje sadrže karbocikličku ili heterocikličku skupinu i pri čemu supstituenti mogu biti jednaki ili različiti, whereby multiple substitutions with cyclic groups or with those groups containing a carbocyclic or heterocyclic group are excluded and wherein the substituents may be the same or different,
i R1 predstavlja fenilnu skupinu koji može biti mono-, di- ili trisupstituirana s atomima fluora, klora ili broma, s alkoksi, trifluormetilnom, nitro, hidroksi ili amino skupinom, pri čemu supstituenti mogu biti jednaki ili različiti, and R1 represents a phenyl group which can be mono-, di- or tri-substituted with fluorine, chlorine or bromine atoms, with an alkoxy, trifluoromethyl, nitro, hydroxy or amino group, whereby the substituents can be the same or different,
i pri čemu sve gore spomenute alkilne i alkoksi skupine i alkilne ili alkilenske skupine prisutne u drugim spomenutim skupinama mogu sadržavati 1 do 3 ugljikova atoma, ako nije navedeno drugačije, njihovi tautomeri, diastereomeri, enantiomeri i njihove soli. and wherein all the aforementioned alkyl and alkoxy groups and the alkyl or alkylene groups present in the other mentioned groups may contain 1 to 3 carbon atoms, unless otherwise stated, their tautomers, diastereomers, enantiomers and their salts.
Najveću posebnu prednost daje se onim spojevima gornje opće formule (I) u kojima The greatest special advantage is given to those compounds of the above general formula (I) in which
R predstavlja 3,4-dihidro-2(1H)-oksokinazolin-3-il, 1,3-dihidro-4-fenil-2H-2-oksoimidazol-1-il, 2,4-dihidro-5-fenil-3(3H)-okso-1,2,4-triazol-2-il, 3,4-dihidro-2(1H)-oksopirido[4,3-d]-pirimidin-3-il, 3,4-dihidro-2(1H)-okso-pirido[3,4-d]pirimidin-3-il ili 1,3-dihidro-2(2H)-okso-imidazo[4,5-c]kinolin-3-ilnu skupinu, R represents 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 2,4-dihydro-5-phenyl-3 (3H)-oxo-1,2,4-triazol-2-yl, 3,4-dihydro-2(1H)-oxopyrido[4,3-d]-pyrimidin-3-yl, 3,4-dihydro- 2(1H)-oxo-pyrido[3,4-d]pyrimidin-3-yl or 1,3-dihydro-2(2H)-oxo-imidazo[4,5-c]quinolin-3-yl group,
pri čemu gore spomenute mono- i bicikličke heterocikličke skupine mogu biti mono- ili disupstituirane u ugljikovom kosturu s atomima fluora, klora ili broma ili mogu biti monosupstituirane sa supstituentom iz niza koji čine 4-metil-1-piperazinil, 2,5-dioksaciklopentilmetoksi, metoksi, 2-(4-morfolinil)etoksi, 2-dimetilaminoetoksi, 3-dimetilaminopropoksi, metoksikarbonilmetoksi, hidroksi-karbonilmetoksi, nitro, trifluormetil, metoksikarbonil, karboksi, hidroksi, aminokarbonil, dietilaminokarbonil, [N-(2-dimetilaminoetil)-N-metilamino]karbonil, [(metoksi-karbonilmetil)amino]karbonil ili [(hidroksikarbonilmetil)-amino]karbonilna skupina, wherein the above-mentioned mono- and bicyclic heterocyclic groups can be mono- or disubstituted in the carbon skeleton with fluorine, chlorine or bromine atoms or can be monosubstituted with a substituent from the series consisting of 4-methyl-1-piperazinyl, 2,5-dioxacyclopentylmethoxy, methoxy, 2-(4-morpholinyl)ethoxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, methoxycarbonylmethoxy, hydroxy-carbonylmethoxy, nitro, trifluoromethyl, methoxycarbonyl, carboxy, hydroxy, aminocarbonyl, diethylaminocarbonyl, [N-(2-dimethylaminoethyl)-N- methylamino]carbonyl, [(methoxy-carbonylmethyl)amino]carbonyl or [(hydroxycarbonylmethyl)-amino]carbonyl group,
i R1 predstavlja fenilnu skupinu, and R1 represents a phenyl group,
koja može biti mono-, di- ili trisupstituirana s atomma fluora, klora ili broma ili s hidroksi ili amino skupinama, pri čemu supstituenti mogu biti jednaki ili različiti, na primjer 4-klorfenil, 4-amino-3,5-dibromfenil ili 3,5-di-brom-4-hidroksifenilna skupina, njihovim tautomerima, diastereomerima, enantiomerima i njihovim solima. which can be mono-, di- or trisubstituted with fluorine, chlorine or bromine atoms or with hydroxy or amino groups, whereby the substituents can be the same or different, for example 4-chlorophenyl, 4-amino-3,5-dibromophenyl or 3 ,5-di-bromo-4-hydroxyphenyl group, their tautomers, diastereomers, enantiomers and their salts.
Slijedeći spojevi navode se kao primjeri posebno prednosnih spojeva: The following compounds are cited as examples of particularly preferred compounds:
(1) cis-3-{1-[2-(4-klorbenzoil)-ciklopropankarbonil]-4-piperidinil}-3,4-dihidro-2(1H)-kinazolinon, (1) cis-3-{1-[2-(4-chlorobenzoyl)-cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone,
(2) trans-1-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropankarbonil]-4-piperidinil}-1,3-dihidro-4-(3-metoksi-fenil)-2 (2H)-imidazolon, (2) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropanecarbonyl]-4-piperidinyl}-1,3-dihydro-4-(3-methoxy-phenyl)-2 (2H)-imidazolone,
(3) trans-3-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropankarbonil]-4-piperidinil}-3,4-dihidro-2(1H)-kinazolinon, (3) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone,
(4) trans-3-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-6-brom-3,4-dihidro-2(1H)- (4) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-6-bromo-3,4-dihydro-2(1H)-
kinazolinon, quinazolinone,
(5) trans-1-{1-[2-{4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil] -4-piperidinil}-1,3-dihidro-4-fenil-2-(2H)- (5) trans-1-{1-[2-{4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-1,3-dihydro-4-phenyl-2-(2H) -
imidazolon, imidazolone,
(6) trans-1-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-1,3-dihidro-4-[3-(trifluor-metil)fenil]-2(2H)-imidazolon, (6) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-1,3-dihydro-4-[3-(trifluoro-methyl )phenyl]-2(2H)-imidazolone,
(7) trans-1-(1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-1,3-dihidro-4-(3-hidroksi- (7) trans-1-(1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-1,3-dihydro-4-(3-hydroxy-
fenil)-2(2H)-imidazolon, phenyl)-2(2H)-imidazolone,
(8) trans-3-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-3,4-dihidro-6-hidroksi-2(1H) -kinazolinon, (8) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-3,4-dihydro-6-hydroxy-2(1H) - quinazolinone,
(9) trans-3-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil] -4-piperidinil}-3,4-dihidro-6-[(1,3-dioksolan-2-il)metoksi]-2(1H)-kinazolinon, (9) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-3,4-dihydro-6-[(1,3-dioxolane) -2-yl)methoxy]-2(1H)-quinazolinone,
(10) trans-1-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-4-(3,4-diklorfenil)-1,3-dihidro-2(2H)-imidazolon, (10) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-4-(3,4-dichlorophenyl)-1,3-dihydro -2(2H)-imidazolone,
(11) trans-3-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidihil]-3,4-dihidro-2(1H)-pirido[4,3- (11) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidyl]-3,4-dihydro-2(1H)-pyrido[4, 3-
d]pirimidinon, d]pyrimidinone,
(12) trans-1-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-1,3-dihidro-4-(2-metoksi- (12) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-1,3-dihydro-4-(2-methoxy-
fenil)-2(2H)-imidazolon, phenyl)-2(2H)-imidazolone,
(13) trans-1-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-4-(3-klorfenil)-1,3-dihidro-2(2H)-imidazolon, (13) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-4-(3-chlorophenyl)-1,3-dihydro-2 (2H)-imidazolone,
(14) trans-1-{1-[2-{4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-1,3-dihidro-4-(3-nitrofenil)-2(2H)-imidazolon, (14) trans-1-{1-[2-{4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-1,3-dihydro-4-(3-nitrophenyl)-2 (2H)-imidazolone,
(15) trans-3-{1-[2-(4-amino-3,5-dibrombenzoil}-ciklopropan-karbonil]-4-piperidinil}-3,4-dihidro-2(1H)-pirido[3,4-d]pirimidinon, (15) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl}-cyclopropane-carbonyl]-4-piperidinyl}-3,4-dihydro-2(1H)-pyrido[3, 4-d]pyrimidinone,
(16) trans-3-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-3,4-dihidro-6-[2-(dimetil-amino)etoksi]-2(1H)-kinazolinon, (16) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-3,4-dihydro-6-[2-(dimethyl-amino )ethoxy]-2(1H)-quinazolinone,
(17) trans-3-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-3,4-dihidro-6-{4-meti1-1-piperazinil)-2(1H)-kinazolinon, (17) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-3,4-dihydro-6-{4-methyl-1- piperazinyl)-2(1H)-quinazolinone,
(18) trans-1-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-1,3-dihidro-4-[2-(trifluor-metil}fenil]-2(2H)-imidazolon, (18) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-1,3-dihydro-4-[2-(trifluoro-methyl }phenyl]-2(2H)-imidazolone,
(19) trans-3-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-3,4-dihidro-6-[3-(dimetil-amino)propoksi]-2(1H)-kinazolinon, (19) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-3,4-dihydro-6-[3-(dimethyl-amino )propoxy]-2(1H)-quinazolinone,
(20) trans-3-{1-[2-(3,5-dibrom-4-hidroksibenzoil)-ciklo-propankarbonil]-4-piperidinil}-3,4-dihidro-2(1H)-kinazolinon, (20) trans-3-{1-[2-(3,5-dibromo-4-hydroxybenzoyl)-cyclo-propanecarbonyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone,
(21) trans-1-{1-[2-(3,5-dibrom-4-hidroksibenzoil)-ciklo-propankarbonil]-4-piperidinil}-1,3-dihidro-4-fenil-2-(2H)-imidazolon, (21) trans-1-{1-[2-(3,5-dibromo-4-hydroxybenzoyl)-cyclopropanecarbonyl]-4-piperidinyl}-1,3-dihydro-4-phenyl-2-(2H) -imidazolone,
(22) trans-3-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-3,4-dihidro-6-(metoksi-karbonilmetoksi)-2(1H)-kinazolinon, (22) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-3,4-dihydro-6-(methoxy-carbonylmethoxy)-2 (1H)-quinazolinone,
(23) trans-3-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-3,4-dihidro-6-(hidroksi-karbonilmetoksi)-2(1H)-kinazolinon, (23) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-3,4-dihydro-6-(hydroxy-carbonylmethoxy)-2 (1H)-quinazolinone,
(24) trans-3-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-3,4-dihidro-6-[2-(4-morfolinil)etoksi]-2(1H)-kinazolinon, (24) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-3,4-dihydro-6-[2-(4-morpholinyl) )ethoxy]-2(1H)-quinazolinone,
(25) trans-3-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-3,4-dihidro-7-metoksi-2(1H)-kinazolinon, (25) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-3,4-dihydro-7-methoxy-2(1H)- quinazolinone,
(26) trans-3-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-3,4-dihidro-7-(metoksi-karbonilmetoksi)-2(1H)-kinazolinon, (26) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-3,4-dihydro-7-(methoxy-carbonylmethoxy)-2 (1H)-quinazolinone,
(27) trans-3-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-7-karboksi-3,4-dihidro-2-(1H)-kinazolinon, (27) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-7-carboxy-3,4-dihydro-2-(1H) -quinazolinone,
(28) trans-3-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-7-metoksikarbonil-3,4-dihidro-2(1H)-kinazolinon, (28) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-7-methoxycarbonyl-3,4-dihydro-2(1H)- quinazolinone,
(29) trans-3-{1-[2-(4-amino-3,5-dibrombenzoil) -ciklopropan-karbonil]-4-piperidinil)-1,3-dihidro-2(2H)-imidazo-[4,5-c]kinolinon, (29) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl)-1,3-dihydro-2(2H)-imidazo-[4 ,5-c]quinolinone,
(30) trans-3-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-3,4-dihidro-7-{[(metoksi-karbonilmetil)amino]karbonil}-2(1H)-kinazolinon, (30) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-3,4-dihydro-7-{[(methoxy-carbonylmethyl) amino]carbonyl}-2(1H)-quinazolinone,
(31) trans-3-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-3,4-dihidro-7-{[N-(2-dimetil-aminoetil)-N-metilamino]karbonil}-2(1H) -kinazolinon, (31) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-3,4-dihydro-7-{[N-(2- dimethylaminoethyl)-N-methylamino]carbonyl}-2(1H)-quinazolinone,
(32) trans-3-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-7-dietilaminokarbonil-3,4- (32) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-7-diethylaminocarbonyl-3,4-
dihidro-2(1H)-kinazolinon, dihydro-2(1H)-quinazolinone,
(33) trans-7-aminokarbonil-3-{1-[2-(4-amino-3,5-dibrom-benzoil)-ciklopropankarbonil]-4-piperidinil}-374-dihidro-2(1H)-kinazolinon, (33) trans-7-aminocarbonyl-3-{1-[2-(4-amino-3,5-dibromo-benzoyl)-cyclopropanecarbonyl]-4-piperidinyl}-374-dihydro-2(1H)-quinazolinone,
(34) trans-3-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-3,4-dihidro-7-{[(hidroksi-karbonilmetil)amino]karbonil}-2(1H)-kinazolinon, (34) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-3,4-dihydro-7-{[(hydroxy-carbonylmethyl) amino]carbonyl}-2(1H)-quinazolinone,
(35) trans-1-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-2,4-dihidro-5-fenil-3(3H)-1,2,4-triazolon, (35) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-2,4-dihydro-5-phenyl-3(3H)- 1,2,4-triazolone,
posebno gore spomenuti spojevi (2), (3:, (5), (7), (8), (9), (13), (19), (22), (23) i (35), i njihove soli. especially the aforementioned compounds (2), (3:, (5), (7), (8), (9), (13), (19), (22), (23) and (35), and their salts.
Spojevi opće formule I se proizvode načelno poznatim postupcima. Slijedeće metode su se pokazale posebno prikladne na pripravu spojeva opće formule I prema izumu: Compounds of the general formula I are produced in principle by known procedures. The following methods have proven to be particularly suitable for the preparation of compounds of the general formula I according to the invention:
a) Povezivanje karboksilne kiseline opće formule a) Connection of a carboxylic acid of the general formula
[image] [image]
u kojoj where
R1 je definiran kao gore, sa spojem opće formule R 1 is defined as above, with a compound of the general formula
[image] [image]
u kojoj where
R je definiran kao gore. R is defined as above.
Povezivanje se provodi ponajprije primjenom metoda poznatih iz kemije peptida (vidi npr. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), na primjer upotrebom karbodiimida kao npr. dicikloheksilkarbodiimida (DCC), diizopropilkarbodiimida (DIC) ili etil-(3-dimetilamino-propil)-karbodiimida, O-(IH-benzotriazol-1-il)-N,N,N',N'-tetrametiluronijevog heksafluorfosfata (HBTU) ili tetra-fluorborata (TBTU) ili 1H-benzotriazol-1-il-oksi-tris-(di-metilamino)-fosfonijevog heksafluorfosfata (BOP). Dodaikom 1-hidroksibenzotriazola (HOBt) ili 3-hidroksi-4-okso-3,4-dihidro-1,2,3-benzotriazina (HOObt) može se, po želji, dodatno potisnutu svaku moguću racemizaciju, ili se može povećati brzinu reakcije. Povezivanje se normalno provodi s ekvimolarnim količinama komponenata povezivanja kao i reagenta povezivanja u otapalima kao što su diklormetan, tetrahidrofuran, acetonitril, dimetilformamid (DMF), dimetilacetamid (DMA), N-metilpirolidon (NMP) ili njihove mješavine i pri teraperaturi između -30 i +30°C, ponajprije -20 i +25°C. Ako je potrebno, kao dodatna pomoćna baza upotrebljava se ponajprije N-etil-diizopropil-amin (DIEA) (Hünigova baza). Coupling is primarily carried out using methods known from peptide chemistry (see e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example using carbodiimides such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or ethyl-( 3-dimethylamino-propyl)-carbodiimide, O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1- yl-oxy-tris-(di-methylamino)-phosphonium hexafluorophosphate (BOP). By adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt), any possible racemization can be further suppressed, or the reaction rate can be increased, if desired. . Coupling is normally carried out with equimolar amounts of coupling components as well as coupling reagents in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between -30 and +30°C, preferably -20 and +25°C. If necessary, N-ethyl-diisopropyl-amine (DIEA) (Hünig's base) is preferably used as an additional auxiliary base.
Takozvani anhidridni postupak se koristi kao daljnja metoda povezivanja za sintezu spojeva opće formule I (vidi također: M. Bodanszky, "Peptide Chemistry", Springer-Verlag 1988, str. 58-59; M. Bodanszky, "Principles of Peptide Synthesis", Springer-Verlag 1984, str. 21-27). Povoljna je Vaughanova inačica postupka miješanih anhidrida (J.R. Vaughan Jr., J. Amer. Chem. Soc. 73, 3547 (1951)), po kojoj se miješani anhidrid karboksilne kiseline opće formule (III), koji se želi povezati, i monoizobutil karbonat dobije upotrebom izobutil klorkarbonata u prisutnosti baze kao što je 4-metil-morfolin ili 4-etilmorfolin. Priprava tog miješanog anhidrida i povezivanje s aminima provodi se postupkom u jednoj posudi upotrebom gore spomenutih otapala i pri temperaturi između -20 i +25°C, ponajprije 0 i +25°C. The so-called anhydride process is used as a further coupling method for the synthesis of compounds of general formula I (see also: M. Bodanszky, "Peptide Chemistry", Springer-Verlag 1988, pp. 58-59; M. Bodanszky, "Principles of Peptide Synthesis", Springer-Verlag 1984, pp. 21-27). Vaughan's version of the mixed anhydride process (J.R. Vaughan Jr., J. Amer. Chem. Soc. 73, 3547 (1951)) is advantageous, by which the mixed anhydride of a carboxylic acid of the general formula (III), which is to be coupled, and monoisobutyl carbonate obtained by using isobutyl chlorocarbonate in the presence of a base such as 4-methyl-morpholine or 4-ethylmorpholine. The preparation of this mixed anhydride and connection with amines is carried out in a one-pot process using the above-mentioned solvents and at a temperature between -20 and +25°C, preferably 0 and +25°C.
b) Povezivanje spoja opće formule b) Connecting compounds of the general formula
[image] [image]
u kojoj where
R1 je definiran kao gore, i R1 is defined as above, i
Nu predstavlja otpusnu skupinu, npr. halogeni atom kao što je atom klora, broma ili joda, alkilsulfoniloksi skupinu s 1 do 10 ugljikovih atoma u alkilnoj skupini, fenilsulfoniloksi ili naftilsulfoniloksi skupinu prema potrebi mono-, di- ili trisupstituiranu s atomima klora ili broma, s metil ili nitro skupinama, dok supstituenti mogu biti jednaki ili različiti, 1H-imidazol-1-il, IH-pirazol-1-il prema potrebi supstituiran s 1 ili 2 metilne skupine u ugljikovom kosturu, 1H-1,2,4-triazol-1-il, 1H-1,2,3-triazol-1-il, 1H-1,2,3,4-tetrazol-1-il, vinil, propargil, p-nitrofenil, 2,4-dinitrofenil, triklorfenil, pentaklor-fenil, pentafluorfenil, piranil ili piridinil, dimetil-aminiloksi, 2 (1H)-oksopiridin-1-iloksi, 2,5-diokso-pirolidin-1-iloksi, ftalimidiloksi, 1H-benzotriazol-1-iloksi ili azidnu skupinu, sa spojem opće formule Nu represents a leaving group, e.g. a halogen atom such as a chlorine, bromine or iodine atom, an alkylsulfonyloxy group with 1 to 10 carbon atoms in the alkyl group, a phenylsulfonyloxy or naphthylsulfonyloxy group optionally mono-, di- or tri-substituted with chlorine or bromine atoms, with methyl or nitro groups, while the substituents can be the same or different, 1H-imidazol-1-yl, 1H-pyrazol-1-yl optionally substituted with 1 or 2 methyl groups in the carbon skeleton, 1H-1,2,4- triazol-1-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3,4-tetrazol-1-yl, vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachloro-phenyl, pentafluorophenyl, pyranyl or pyridinyl, dimethyl-aminyloxy, 2 (1H)-oxopyridin-1-yloxy, 2,5-dioxo-pyrrolidin-1-yloxy, phthalimidyloxy, 1H-benzotriazol-1-yloxy or azide group, with a compound of the general formula
[image] [image]
u kojoj where
R je definiran kao gore. R is defined as above.
Reakciju se provodi pod Schotten-Baumannovim ili Einhornovim uvjetima, tj. komponente reagiraju u prisutnosti najmanje jednog ekivalenta pomoćne baze pri temperaturi između -50°C i +120°C, ponajprije -10°C i +30°C, i prema potrebi u prisutnosti otapala. Kao pomoćne baze upotrebljavaju se ponajprije hidroksidi alkalijskih metala i hidroksidi zemno alkalijskih metala, npr. Natrijev hidroksid, kalijev hidroksid ili barijev hidroksid, karbonati alkalijskih metala, npr. natrijev karbonat, kalijev karbonat ili cezijev karbonat," acetati alkalijskih metala, npr. natrijev ili kalijev acetat, kao i tercijarni amini, npr. piridin, 2,4,6-trimetilpiridin, kinolin, trietilamin, N-etil-diizopropilamin, N-etil-dieikloheksil-amin, 1,4-diazabiciklo[2,2,2]oktan ili 1,8-diazabiciklo-[5,4,0]undec-7-en, a kao otapalo se može upotrijebiti, na primjer, diklormetan, tetrahidrofuran, 1,4-dioksan, aceto-nitril, dimetilformamid, dimetilacetamid, N-metil pirolidon ili njihove mješavine; ako se kao pomoćna baza upotrebljavaju hidroksidi alkalijskih metala ili hidroksidi zemno alkalijskih metala, karbonati ili acetati alkalijskih metala, u reakcijsku smjesu se također može dodati vodu kao ko-otapalo. The reaction is carried out under Schotten-Baumann or Einhorn conditions, i.e. the components react in the presence of at least one equivalent of an auxiliary base at a temperature between -50°C and +120°C, preferably -10°C and +30°C, and if necessary in presence of solvent. Alkali metal hydroxides and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, e.g. sodium carbonate, potassium carbonate or cesium carbonate, alkali metal acetates, e.g. sodium or potassium acetate, as well as tertiary amines, eg pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexyl-amine, 1,4-diazabicyclo[2,2,2] octane or 1,8-diazabicyclo-[5,4,0]undec-7-ene, and the solvent can be, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethylformamide, dimethylacetamide, N -methyl pyrrolidone or their mixtures; if hydroxides of alkali metals or hydroxides of alkaline earth metals, carbonates or acetates of alkali metals are used as auxiliary bases, water can also be added to the reaction mixture as a co-solvent.
c) Ciklopropanizacija spoja opće formule c) Cyclopropanization of a compound of the general formula
[image] [image]
u kojoj where
R i R1 su definirani kao gore. R and R1 are defined as above.
Ciklopropanizaciju se može provesti katalitički s diazometanom, upotrebom polaznih spojeva formule (V) u kojima olefinska dvostruka veza ima ponajprije (E)-konfigaciju. Reakciju se provodi pri temperaturi između 0°C i + 50°C, ponajprije pri sobnoj temperature. Povoljni katalizatori su paladij (II) spojevi, na primjer PdCl2(FCN)2 ili paladij(II) acetat Pd3(OAc)6. Prikladna otapala uključuju inertne etere, na primjer dietil eter, ugljikovodike i ponajbolje klorirane ugljikovodike kao što je diklormetan ili 1,2-dikloretan, ili mješavine tih otapala (vidi također: H. Abdallah, R. Green i-R. Carrie,Tetrahedron Letters 23, 503-506 (1982)). Ciklopropanizaciju spojeva opće formule V s (E)-konfiguracijom može se također učiniti asimetričnom "upotrebom semicorrin" bakrenog katalizatora koji je opisao A. Pfaltz, Acc. Chem. Res. 26, 339-345 (1993), čime se dobije visoki enantiomerni višak. Potreban diazometan se također može proizvesti in situ dodatkom u mješavinu alkena opće formule (V) u obrocima N-metil-N-nitrozouree, paladijevog katalizatora, organskog otapala i 40% do 50% vodene otopine kalijevog hidroksida; tom metodom, potrebna su općenito najviše 2 mola N-metil-N-nitrozouree po molu alkena opće formule (V). Osim toga, Ciklopropanizacija alkena opće formule (V) u kojoj olefinska dvostruka veza može biti u bilo kojem smjeru, a prednosno ima (E)-konfiguraciju, može se provesti analogno takozvanoj Simmons-Smithovoj reakciji s dijod-metanom i parom cink/bakar (vidi također: Simmons, Cairns, Vladuchik i Hoiness, Org. React. 20, 1-131 (1973); Furukawa i Kawabata, Adv. Organomet. Chem. 12, 83-134 (1974)) ili parom cink/srebro (vidi također: J. M. Denis, C. Girard i J. M. Conia, Synthesis 1972, 549). Par cink/bakar može se proizvesti brojnim alternativnim metodama (vidi na primjer: Shank i Shechter, J. Org. Chem. 24, 1525 (1959); LeGoff, J. Org. Chem. 29, 2048 (1964)), pri čemu je posebno prikladno grijanje cinkovog praha s bakrenim(I) kloridom u dietil eteru i pod dušikom (Rawson i Harrison, J. Org. Chem. 35, 2057 (1970)). Reakcija se također odvija s ne-aktiviranim cinkom u ultrazvučnoj kupelji (vidi također: Repič i Vogt, Tetrahedron Letters 23, 2729 (1982); Repič, Lee i Giger, Org. Prep. Proced. Int. 16, 25 (1984). Spoj koji napada alkene opće formule (V) je organo-cinkov spoj koji nastaje kao intermedijat, bis-(jodmetil)-cink (vidi također: Georg Wittig i Frank Wingler, Chem. Ber. 97, 2146 (1964)) ili adukt (JCH2)2Zn·ZnJ2 (Blanchard i Simmons, J. Amr Chem. Soc. 86, 1337 (1964)), čije otopine su dovoljno postojane za fizičko-kemijska istraživanja. Ciklopropanizacija se odvija stereospecifično sin. Reaktivnbst reagenta može se povisiti dodatkom Lewisove kiseline, na primjer nikal(II) bromida (vidi također: H. Kanai et al., Buli. Chem. Soc. Jap. 56, 1025-1029 (1983), Synthesis 1984, 987), dok se potreban dijodmetan također može proizvesti in situ iz dikrom-metana i natrijevog jodida. U drugoj inačici ciklopropanizacije polazni materijal opće formule (V) reagira s dijodmetanom ili s drugim dihalometanom i dietilcinkom (vidi također: Furukawa, Kawabata i Nishimura, Tetrahedron 24, 53 (1968), Tetrahedron Letters 1968, 3495; Nishimura, Kawabata i Furukawa, Tetrahedron 25, 2647 (1969); Miyano i Hashimoto, Buli. Chem. Soc. Jpn. 46, 892 (1973); Friedrich i Biresaw, J. Org. Cherru 47, 1615 (1982)}. Konačno, potreban reagent može se također proizvesti iz diihalometana i bakra (Kawabata, Kamemura i Naka, J. Am. Chem. Soc. 101, 2139 (1979); Kawabata, Tanimoto i Fujiwara, Tetrahedron 35, 1919 (1979)). Ciklopropanizaciju se prevodi pri temperaturi između 0°C i +70°C, ponajprije pri sobnoj temperaturi, i upotrebom eterskog otapala, na primjer dietil etera ili tetrahidrofurana. Cyclopropanization can be carried out catalytically with diazomethane, using the starting compounds of the formula (V) in which the olefinic double bond preferably has the (E)-configuration. The reaction is carried out at a temperature between 0°C and + 50°C, preferably at room temperature. Favorable catalysts are palladium(II) compounds, for example PdCl2(FCN)2 or palladium(II) acetate Pd3(OAc)6. Suitable solvents include inert ethers, for example diethyl ether, hydrocarbons and preferably chlorinated hydrocarbons such as dichloromethane or 1,2-dichloroethane, or mixtures of these solvents (see also: H. Abdallah, R. Green and-R. Carrie, Tetrahedron Letters 23, 503-506 (1982)). Cyclopropanation of compounds of general formula V with (E)-configuration can also be done asymmetric "using the semicorrin" copper catalyst described by A. Pfaltz, Acc. Chem. Crisp. 26, 339-345 (1993), giving a high enantiomeric excess. The required diazomethane can also be produced in situ by addition to a mixture of alkenes of general formula (V) in portions of N-methyl-N-nitrosourea, a palladium catalyst, an organic solvent and 40% to 50% aqueous potassium hydroxide; with this method, a maximum of 2 moles of N-methyl-N-nitrosourea per mole of alkene of general formula (V) is generally required. In addition, cyclopropanization of alkenes of the general formula (V) in which the olefinic double bond can be in any direction, preferably having the (E)-configuration, can be carried out analogously to the so-called Simmons-Smith reaction with diiodo-methane and a zinc/copper pair ( see also: Simmons, Cairns, Vladuchik and Hoiness, Org. React. 20, 1-131 (1973); Furukawa and Kawabata, Adv. Organomet. Chem. 12, 83-134 (1974)) or with zinc/silver vapor (see also: J.M. Denis, C. Girard and J.M. Conia, Synthesis 1972, 549). The zinc/copper couple can be produced by a number of alternative methods (see, for example, Shank and Shechter, J. Org. Chem. 24, 1525 (1959); LeGoff, J. Org. Chem. 29, 2048 (1964)), wherein heating zinc dust with copper(I) chloride in diethyl ether under nitrogen is particularly convenient (Rawson and Harrison, J. Org. Chem. 35, 2057 (1970)). The reaction also takes place with non-activated zinc in an ultrasonic bath (see also: Repic and Vogt, Tetrahedron Letters 23, 2729 (1982); Repic, Lee and Giger, Org. Prep. Proced. Int. 16, 25 (1984). The compound which attacks alkenes of general formula (V) is an organo-zinc compound formed as an intermediate, bis-(iodomethyl)-zinc (see also: Georg Wittig and Frank Wingler, Chem. Ber. 97, 2146 (1964)) or adduct ( JCH2)2Zn·ZnJ2 (Blanchard and Simmons, J. Amr Chem. Soc. 86, 1337 (1964)), the solutions of which are stable enough for physicochemical studies. , for example nickel(II) bromide (see also: H. Kanai et al., Buli. Chem. Soc. Jap. 56, 1025-1029 (1983), Synthesis 1984, 987), while the required diiodomethane can also be produced in sieve from dichloromethane and sodium iodide In another version of cyclopropanization, the starting material of the general formula (V) reacts with diiodomethane or with another dihalomethane and diethylzinc (see also: Furukawa, Kawabata and Nishimura, Tetrahedron 24, 53 (1968), Tetrahedron Letters 1968, 3495; Nishimura, Kawabata and Furukawa, Tetrahedron 25, 2647 (1969); Miyano and Hashimoto, Buli. Chem. Soc. Jpn. 46, 892 (1973); Friedrich and Biresaw, J. Org. Cherru 47, 1615 (1982)}. Finally, the required reagent can also be produced from dihalomethane and copper (Kawabata, Kamemura and Naka, J. Am. Chem. Soc. 101, 2139 (1979); Kawabata, Tanimoto and Fujiwara, Tetrahedron 35, 1919 (1979)). The cyclopropanization is carried out at a temperature between 0°C and +70°C, preferably at room temperature, and using an ethereal solvent, for example diethyl ether or tetrahydrofuran.
Ciklopropanizaciju alkena opće formule (V) u kojem olefinska dvostruka veza može imati bilo koju željenu orijentaciju, a prednosno (E) konfiguraciju, može se također provesti s dimetiloksosulfonijevim metilidom formule Cyclopropanation of alkenes of the general formula (V) in which the olefinic double bond can have any desired orientation, preferably (E) configuration, can also be carried out with dimethyloxosulfonium methylide of the formula
[image] [image]
ili s dialkilamino-oksosulfonijevim metilidom opće formule or with dialkylamino-oxosulfonium methylide of the general formula
[image] [image]
u kojoj where
R2 predstavlja metilnu ili etilnu skupinu. R2 represents a methyl or ethyl group.
Reakcija se provodi u dipolarnom aprotonskom otapalu, ponajprije u dimetilsulfoksidu, i pri temperaturi između +10 i +80°C, ponajprije +20 i +60°C. Oksosulfonijevi ilidi VI i VII mogu se staviti kao takovi, međutim oni se također proizvode in situ iz trimetiloksosulfonijevog jodida formule The reaction is carried out in a dipolar aprotic solvent, preferably in dimethylsulfoxide, and at a temperature between +10 and +80°C, preferably +20 and +60°C. The oxosulfonium ylides VI and VII can be inserted as such, but they are also produced in situ from trimethyloxosulfonium iodide of the formula
[image] [image]
djelovanjem metansulfinilmetil natrija (vidi također: E. J. Corey i M. Chaykowski, J. Am. Chem. Soc. 87, 1353 (1965), Org. Syn. 49, 78 (1969); H. Schmidbauer i W. Tronich, Tetrahedron Letters 1968, 5335) ili iz dialkilamino-oksosulfonijevog jodida opće formule by the action of methanesulfinylmethyl sodium (see also: E. J. Corey and M. Chaykowski, J. Am. Chem. Soc. 87, 1353 (1965), Org. Syn. 49, 78 (1969); H. Schmidbauer and W. Tronich, Tetrahedron Letters 1968, 5335) or from dialkylamino-oxosulfonium iodide of the general formula
[image] [image]
u kojoj where
R2 je definiran kao gore, R2 is defined as above,
djelovanjem natrijevog hidrida (vidi također: C.R. Johnson, E.R. Janiga i M. Haake, J. Am. Chem. Soc. 90, 3890 (1968); C.R. Johnson i C. W. Schroeck, J. Am. Chem. Soc. 90, 6852 (1968); C.R. Johnson i G.F. Katekar, J. Am. Chem. Soc. 92, 5753 (1970); C.R. Johnson, M. Haake i C.W. Schroeck, J. Am. Chem. Soc. 92, 6594 (1970); C.R. Johnson i P.E. Rogers, J. Org. Chem. 38, 1793 (1973) u dimetilsulfoksidu. Ilidi opće formule VII-mogu se također dobiti u optički aktivnom oblku i oni su tako prikladni za asimetričnu sintezu spojeva opće formule (I). by the action of sodium hydride (see also: C.R. Johnson, E.R. Janiga and M. Haake, J. Am. Chem. Soc. 90, 3890 (1968); C.R. Johnson and C. W. Schroeck, J. Am. Chem. Soc. 90, 6852 ( 1968); C.R. Johnson and G.F. Katekar, J. Am. Chem. Soc. 92, 5753 (1970); C.R. Johnson, M. Haake and C.W. Schroeck, J. Am. Chem. Soc. 92, 6594 (1970); C.R. Johnson and P. E. Rogers, J. Org. Chem. 38, 1793 (1973) in dimethylsulfoxide. The ylides of general formula VII- can also be obtained in an optically active form and are thus convenient for the asymmetric synthesis of compounds of general formula (I).
d) Za pripravu-spoja opće formule I, u kojoj najmanje jedna od skupina R i R1 sadrži jednu ili više karboksi skupina, provodi se alkalijska saponifikacija estera karboksilne kiseline opće formule d) For the preparation of the compound of the general formula I, in which at least one of the groups R and R1 contains one or more carboxyl groups, alkaline saponification of the carboxylic acid ester of the general formula is carried out
[image] [image]
u kojoj where
Ra i R1d imaju gore data značenja za R i R1, pod uvjetom da najmanje jedna od tih skupina sadrži jednu ili više alkoksikarbonilnih skupina, Ra and R1d have the meanings given above for R and R1, provided that at least one of these groups contains one or more alkoxycarbonyl groups,
i, po želji, zatim se obradi s razrijeđenom organskom ili anorganskom kiselinom da se oslobodi bazičnu karboksilnu kiselinu iz soli koja nastane prva. and, if desired, then treated with a dilute organic or inorganic acid to liberate the basic carboxylic acid from the first formed salt.
Za alkalijsku saponifikaciju estera opće formule (Ia), povoljni su litijev hidroksid, natrijev hidroksid i kalijev hidroksid; međutim, također su prikladni i drugi hidroksidi alkalijskih metala kao što je cezijev hidroksid, ili hidroksidi zemno alkalijskih metala, na primjer barijev hidroksid, ili tetralkilamonijev hidroksid. Postupak se provodi u vodenoj otopini i korisno s dodatkom ko-otapala koje se miješa s vodom, ponajprije alkohola kao što je metanol, etanol ili 2-etoksietanol, ili etera kao što je tetrahidrofuran ili 1,4-dioksan. Prikladna temperatura za alkalijsku saponifikaciju je između -10°C i vrelišta upotrijebljene mješavine vode i otapala, a ponajprije sobna temperatura. Za oslobađanje bazične karboksilne kiseline iz njezine soli koja nastaje prva, prikladne su razrijeđene vodene organske ili anorganske kiseline, npr. octena kiselina, oksalna kiselina, metansulfon~ska kiselina, solna kiselina, sumporna kiselina i fosforna kiselina. For alkaline saponification of esters of general formula (Ia), lithium hydroxide, sodium hydroxide and potassium hydroxide are advantageous; however, other alkali metal hydroxides such as cesium hydroxide, or alkaline earth metal hydroxides, for example barium hydroxide, or tetraalkylammonium hydroxide, are also suitable. The process is carried out in an aqueous solution and usefully with the addition of a water-miscible co-solvent, preferably an alcohol such as methanol, ethanol or 2-ethoxyethanol, or an ether such as tetrahydrofuran or 1,4-dioxane. The appropriate temperature for alkaline saponification is between -10°C and the boiling point of the water and solvent mixture used, preferably room temperature. Dilute aqueous organic or inorganic acids, for example acetic acid, oxalic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid, are suitable for the release of the basic carboxylic acid from its first formed salt.
e) Za pripravu spoja opće formule I u kojoj skupina R u ugljikovom kosturu je također mono-, di- ili tri-supstituirana sa supstituentom iz niza koji čine amino-karbonil, alkilaminokarbonil, dialkilaminokarbonil, [N-alkil-N-(dialkil-aminoalkil)amino]karbonil, hidroksi-karbonilalkilaminokarbonil, alkoksikarbonilalkilaminokarbonil, (4-morfolinil) karbonil, (1-pirolidinil)karbonil, (1-piperidinil)karbonil, (heksahidro-1-azepinil)karbonil ili (4-metil-1-piperazinil)karbonilna skupina: e) For the preparation of compounds of the general formula I in which the group R in the carbon skeleton is also mono-, di- or tri-substituted with a substituent from the series consisting of amino-carbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, [N-alkyl-N-(dialkyl- aminoalkyl)amino]carbonyl, hydroxy-carbonylalkylaminocarbonyl, alkoxycarbonylalkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl or (4-methyl-1-piperazinyl)carbonyl )carbonyl group:
Povezivanje spoja opće formule Connecting compounds of the general formula
[image] [image]
u kojoj where
R1 je definiran kao gore i R1 is defined as above and
skupina Rb ima značenje dato ranije gore za R, pod uvjetom da je ona mono-, di- ili trisupstituirana u ugljikovom kosturu s karboksi skupinom, the group Rb has the meaning given above for R, provided that it is mono-, di- or trisubstituted in the carbon skeleton with a carboxy group,
s amonijakom, alkilaminima, N-alkil-N-(dialkilamino-alkil)aminima, hidroksikarbonilalkilaminima, alkoksi-karbonilalkilaminima ili dialkilaminima, na primjer 1-metil-piperazinom, morfolinom, pirolidinom, piperidinom ili heksahidroazepinom. with ammonia, alkylamines, N-alkyl-N-(dialkylamino-alkyl)amines, hydroxycarbonylalkylamines, alkoxy-carbonylalkylamines or dialkylamines, for example 1-methyl-piperazine, morpholine, pyrrolidine, piperidine or hexahydroazepine.
Povezivanje se provodi ponajprije primjenom metoda poznatih iz kemije peptida (vidi, npr. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), na primjer upotrebom karbodiimida kao što je npr. dicikloheksil-karbodiimid (DCC), diizopropil karbodiimid (DIC) ili etil-(3-dimetilamino-propil)-karbodiimid. O-(1H-benzotriazol-1-il)-N,N,N',N'-tetrametiluronijev heksafluorfgsfat (HBTU) ili tetrafluorborat (TBTU) ili 1H-benzotriazoI-1-il-oksi-tris-(dimetilamino)-fosfonijev heksafluorfosfat (BOP). Dodatkom 1-hidroksibenzotriazola (HOBt) ili 3-hidroksi-4-okso-3,4-dihidro-1,2,3-benzotriazina (HOObt) može se, po želji, dodatno potisnuti svaku moguću racemizaciju ili se može povećati brzinu reakcije. Povezivanje se normalno provodi s ekvimolarnim količinama kompomenata povezivanja kao i reagenta za povezivanje u otapalu kao što je diklor-metan, tetrahidrofuran, acetonitril, dimetilforniamid (DMF), dimetilacetamid (DMA), N-metilpirolidon (NMP) ili njihove mješavine i pri temperaturi između -30 i +30°C, ponajprije između -20 i +25°C. Coupling is primarily carried out using methods known from peptide chemistry (see, e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example using carbodiimides such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide ( DIC) or ethyl-(3-dimethylamino-propyl)-carbodiimide. O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). The addition of 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt) can, if desired, further suppress any possible racemization or increase the reaction rate. Coupling is normally carried out with equimolar amounts of coupling components as well as coupling reagents in a solvent such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylforniamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at a temperature between -30 and +30°C, preferably between -20 and +25°C.
Ako je potrebno, kao dodatna pomoćna baze povoljno se može upotrijebiti N-etil-diizopropilamin (DIEA) (Hünigova baza). If necessary, N-ethyl-diisopropylamine (DIEA) (Hünig's base) can advantageously be used as an additional auxiliary base.
Takozvani anhidridni postupak koristi se kao daljnja metoda povezivanja za sintezu spojeva opće formule I (vidi također: M. Bodanszky, "Peptide Chemistry", Springer-Verlag 1988, str. 58-59; M. Bodanszky, "Principles of Peptide Synthesis", Springer-Verlag 1984, str. 21-27). Vaughanova inačica postupka s miješanim anhidridom ima prednost (J.R. Vaughan Jr., J. Amer. Chem. Soc. 73, 3547 (1951)), po kojoj se miješani anhidrid karboksilne kiseline opće formule (III), koju se želi povezati, i monoizobutil karbonata dobije upotrebom izobutil klorkarbonata u prisutnosti baze kao što je 4-metil-morfolin ili 4-etilmorfolin. Priprava tog miješanog anhidrida i povezivanje s aminom se provodi postupkom u jednoj posudi, upotrebom gore spomenutih otapala i pri temperaturi između -20 i +25°C, ponajprije između 0 i +25°C. The so-called anhydride process is used as a further coupling method for the synthesis of compounds of general formula I (see also: M. Bodanszky, "Peptide Chemistry", Springer-Verlag 1988, pp. 58-59; M. Bodanszky, "Principles of Peptide Synthesis", Springer-Verlag 1984, pp. 21-27). Vaughan's version of the mixed anhydride process is preferred (J.R. Vaughan Jr., J. Amer. Chem. Soc. 73, 3547 (1951)), by which the mixed anhydride of a carboxylic acid of the general formula (III), to be coupled, and monoisobutyl of carbonate is obtained by using isobutyl chlorocarbonate in the presence of a base such as 4-methyl-morpholine or 4-ethylmorpholine. The preparation of this mixed anhydride and the connection with the amine is carried out in a one-pot process, using the above-mentioned solvents and at a temperature between -20 and +25°C, preferably between 0 and +25°C.
Novi ciklopropani opće formule (I) prema izumu sadrže najmanje jedno kiralno središte. Ponekad se spojevi mogu -dobiti u obliku dva diastereomerna para antipoda. Izum uključuje pojedinačne izomere i njihove smjese. The new cyclopropanes of general formula (I) according to the invention contain at least one chiral center. Sometimes compounds can be obtained in the form of two diastereomeric pairs of antipodes. The invention includes individual isomers and mixtures thereof.
Diastereomeri se mogu rastaviti na osnovi njihovih različitih fizičko-kemijskih svojstava, npr. frakcijskom kristalizacijom iz prikladnog otapala, visokotlačnom tekućinskom ili kromatografijom na stupcu, upotrebom kiralnih ili ponajprije ne-kiralnih stacionarnih faza. Diastereomers can be resolved on the basis of their different physicochemical properties, eg by fractional crystallization from a suitable solvent, high pressure liquid or column chromatography, using chiral or preferably non-chiral stationary phases.
Racemati koje obuhvaća opća formula (I) mogu se rastaviti, na primjer, pomoću HPLC na prikladnim kiralnim štationarnim fazama (npr. Chiral AGP, Chiralpak AD). Racemati koji sadrže bazične ili kisele funkcionalne skupine mogu se također rastaviti preko diastereomernih, optički aktivnih soli koje se dobiju reakcijom s optički aktivnom kiselinom, na primjer (+) ili (-)-vinskom kiselinom, (+) ili (-)-diacetil vinskom kiselinom, (+) ili (-)-monometil vinskom ili (+)-kamforsulfonskom kiselinom, ili s optički aktivnom bazom, na primjer s (R)-(+)-1-fenil-etilaminom, (S)-(-)-1-feniletilaminom ili (S)-brucinom. Racemates of general formula (I) can be resolved, for example, by HPLC on suitable chiral stationary phases (eg Chiral AGP, Chiralpak AD). Racemates containing basic or acidic functional groups can also be resolved via diastereomeric, optically active salts obtained by reaction with an optically active acid, for example (+) or (-)-tartaric acid, (+) or (-)-diacetyl tartaric acid acid, (+) or (-)-monomethyl tartaric or (+)-camphorsulfonic acid, or with an optically active base, for example with (R)-(+)-1-phenyl-ethylamine, (S)-(-) -1-phenylethylamine or (S)-brucine.
U skladu s konvencionalnom metodom za rastavljanje izomera, racemat spoja opće formule (I) reagira s jednom od gore spomenutih optički aktivnih kiselina ili baza u ekvimolarnoj količini otapala i njegove dobivene kristalinične, diastereomerne, optički aktivne soli se rastave na osnovi njihovih različitih topivosti. Tu se reakciju može provesti u bilo kojem tipu otapala pod uvjetom da su dovoljno različita u pogledu topivosti soli. Upotrebljavaju se ponajprije metanol, etanol ili njihove mješavine, na primjer u volumnom omjeru od 50:50. Zatim se svaka optički aktivna sol otopi u vodi, neutralizira se s bazom kao što je natrijev karbonat ili kalijev karbonat, otopina natrijevog hidroksida ili otopina kalijevog hidroksida i na taj način dobije se odgovarajući slobodan spoj u (+) ili (-) obliku. In accordance with the conventional method for the resolution of isomers, the racemate of the compound of general formula (I) is reacted with one of the aforementioned optically active acids or bases in an equimolar amount of solvent and its resulting crystalline, diastereomeric, optically active salts are resolved on the basis of their different solubilities. This reaction can be carried out in any type of solvent provided that they are sufficiently different in terms of salt solubility. Preferably, methanol, ethanol or their mixtures are used, for example in a volume ratio of 50:50. Each optically active salt is then dissolved in water, neutralized with a base such as sodium carbonate or potassium carbonate, sodium hydroxide solution, or potassium hydroxide solution to obtain the corresponding free compound in (+) or (-) form.
(R) ili (S) enantiomer sam ili smjesa dvaju optički aktivnih diastereomernih spojeva Koje obuhvaća opća formula I mogu se također dobiti provedbom gore opisane sinteze s odgovarajućim reakcijskim komponentama u (R) ili (S) konfiguraciji. The (R) or (S) enantiomer alone or a mixture of two optically active diastereomeric compounds comprising the general formula I can also be obtained by carrying out the synthesis described above with the corresponding reaction components in the (R) or (S) configuration.
Polazni spojevi opće formule (1a) i (1b) mogu se proizvesti metodama a) do c) koje su opisane u ovoj patentnoj prijavi. Polazni materijali opće formule II potrebni za sintezu spojeva opće formule I, ako već nisu poznati iz literature, mogu se lako proizvesti na primjer iz odgovarajućih estera karboksilne kiseline, kao što su metil ili etil esteri, saponifikacijom s vodenom otopinom litijevog, natrijevog ili kalijevog hidroksida i zatim se otopinu zakiseli sa solnom kiselinom analogno metodama koje su poznate u struci. Karboksilati potrebni za ovu reakciju mogu se dobiti iz odgovarajućih 4-aril- ili hetaril-4-okso-2-butenoata, na primjer reakcijom s dimetiloksosulfonijevim metilidom analogno postupku opisanom gore u c). Konačno, 4-aril- ili hetaril-4-okso-2-butenoati su poznati iz literature ili se mogu lako dobiti iz 4-aril- ili hetaril-4-okso-2-butenske kiseline koje su poznate iz literature (vidi također objavljene njemačke patentne prijave 047 806 i 2 103 749). The starting compounds of the general formula (1a) and (1b) can be produced by methods a) to c) which are described in this patent application. The starting materials of general formula II required for the synthesis of compounds of general formula I, if not already known from the literature, can be easily prepared for example from the corresponding carboxylic acid esters, such as methyl or ethyl esters, by saponification with an aqueous solution of lithium, sodium or potassium hydroxide and then acidify the solution with hydrochloric acid analogously to methods known in the art. The carboxylates required for this reaction can be obtained from the corresponding 4-aryl- or hetaryl-4-oxo-2-butenoates, for example by reaction with dimethyloxosulfonium methylide analogously to the procedure described above in c). Finally, 4-aryl- or hetaryl-4-oxo-2-butenoates are known from the literature or can be easily obtained from 4-aryl- or hetaryl-4-oxo-2-butenoic acid which are known from the literature (see also published German patent applications 047 806 and 2 103 749).
Sekundarni amini opće formule III su poznati ili se mogu sintetizirati, na primjer analogno postupcima opisanim u W0 98/11128. Secondary amines of the general formula III are known or can be synthesized, for example analogously to the procedures described in WO 98/11128.
Polazni spojevi opće formule IV mogu se dobiti iz polaznih spojeva opće formule II sa sadašnjim metodama. The starting compounds of the general formula IV can be obtained from the starting compounds of the general formula II by the present methods.
Polazni spojevi opće formule V mogu se lako proizvesti na primjer aciliranjem spojeva formule (III) s derivatima nezasićenih karboksilnih kiselina. The starting compounds of the general formula V can be easily prepared, for example, by acylating compounds of the formula (III) with derivatives of unsaturated carboxylic acids.
Dobiveni spojevi opće formule I, ako-sadrže prikladnu bazičnu funcionalnu skupinu, mogu se prevesti, posebno za farmceutsku upotrebu, u njihove fiziološki prihvatljive soli s anorganskim ili organskim kiselinama. Prikladne kiseline uključuju, na primjer, solnu kiselinu, bromovodičnu kiselinu, fosfornu kiselinu, dušičnu kiselinu, sumpornu kiselinu, metansulfonsku kiselinu, p-toluen-sulfonsku kiselinu, octenu kiselinu, fumarnu kiselinu, sukcinsku kiselinu, mliječnu kiselinu, bademovu kiselinu, jabučnu kiselinu, limunsku kiselinu, vinsku kiselinu ili maleinsku kiselinu. The obtained compounds of the general formula I, if they contain a suitable basic functional group, can be converted, especially for pharmaceutical use, into their physiologically acceptable salts with inorganic or organic acids. Suitable acids include, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid or maleic acid.
Osim toga, ako novi spojevi formule (I) sadrže kiselu funkcionalnu skupinu, na primjer karboksi skupinu, oni se mogu, po želji, prevesti u njihove adicijske soli s anorganskim ili organskim bazema, posebno za farmaceutsku upotrebu u njihove fiziološki prihvatljive adicijske soli. Prikladne baze za tu svrhu jesu, na primjer, natrijev hidroksid, kalijev hidroksid, amonijak, cikloheksilamin, dicikloheksilamin, etanolamin, dietanolamin i trietanol-amin. In addition, if the new compounds of formula (I) contain an acidic functional group, for example a carboxy group, they can, if desired, be converted into their addition salts with inorganic or organic bases, especially for pharmaceutical use into their physiologically acceptable addition salts. Suitable bases for this purpose are, for example, sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
Novi spojevi opće formule I i njihove fiziološki prihvatljive soli imaju CGRP-antagonistička svojstva i pokazuju dobar afinitet u proučavanju vezanja CGRP receptora. Ovi spojevi pokazuju CGRP-antagonistička svojstva u sistemu farmakoloških pokusa koji su opisani u nastavku. The new compounds of general formula I and their physiologically acceptable salts have CGRP-antagonistic properties and show good affinity in the study of CGRP receptor binding. These compounds show CGRP-antagonistic properties in the system of pharmacological experiments described below.
Slijedeći pokusi su bili provedeni da se pokaže afinitet spojeva opće formule I prema humanim CGRP-receptorima i njihova antagonistička svojstva: The following experiments were performed to demonstrate the affinity of the compounds of general formula I for human CGRP-receptors and their antagonistic properties:
A. Proučavanje vezanja sa stanicama SK-N-MC (koje ekspresioniraju humani CGRP receptor) A. Study of binding to SK-N-MC cells (expressing the human CGRP receptor)
SK-N-MC stanice su uzgojene u "Dulbeccovom modiTicianom Eagle mediju". Medij je odstranjeni iz srašćenih kultura. Stanice su isprane dva puta s puferom PBS (Gibco 041-04190_ M), odvojene dodatkom pufera PBS, promiješane s 0,02% EDTA, zatim su ponovno odvojene i-izoliranje centrifugiranjem. Nakon ponovnog suspendiranja u 20 ml "izbalansirane otopine _soli" [BSS (u mM) : NaCl 120, KCl 5,4, NaHCO3 16,2, MgSO4 0,8, NaHPO4 1,0, CaCl2 1,8, D-glukoze 5,5, HEPES 30, pH 7,40] stanice su centrifugirane dva puta pri 100 x g i ponovno suspendirane u BSS-u. Nakon utvrđivanja broja stanica, stanice su homogenizirane u Ultra-Turraxu i centrifugirane 10 minuta pri 3000 x g. Supernatant je odbačen i talog je ponovno centrifugiran u Tris puferu (10 mM Tris, 50 mM NaCl, 5 mM MgCl2, 1 mM EDTA, pH 7,40), nadopunjen je s 1% albumina iz goveđeg seruma i 0,1% bacitracina) i ponovno suspendiran (1 ml/1000000 stanica). Homogenizirani proizvod je smrznut pri -80°C. Pod tim uvjetima, pripravci membrana su postojani više od 6 tjedana. SK-N-MC cells were cultured in "Dulbecco's modiTician Eagle medium". The medium was removed from the confluent cultures. Cells were washed twice with PBS buffer (Gibco 041-04190_M), detached by addition of PBS buffer, mixed with 0.02% EDTA, then detached again and isolated by centrifugation. After resuspension in 20 ml of "balanced _salt solution" [BSS (in mM) : NaCl 120, KCl 5.4, NaHCO3 16.2, MgSO4 0.8, NaHPO4 1.0, CaCl2 1.8, D-glucose 5 ,5, HEPES 30, pH 7.40] cells were centrifuged twice at 100 x g and resuspended in BSS. After determining the number of cells, the cells were homogenized in an Ultra-Turrax and centrifuged for 10 minutes at 3000 x g. The supernatant was discarded and the pellet was centrifuged again in Tris buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCl2, 1 mM EDTA, pH 7.40), was supplemented with 1% bovine serum albumin and 0.1% bacitracin) and resuspended (1 ml/1000000 cells). The homogenized product was frozen at -80°C. Under these conditions, the membrane preparations are stable for more than 6 weeks.
Nakon odmrzavanja, homogenizirani proizvod je razrijeđen 1:10 s puferom za pokuse (50 mM Tris, 150 mM NaCl, 5 mM MgCl2, 1 mM EDTA, pH 7,40) i homogeniziran 30 sekundi u Ultra-Turraxu. 230 μl homogeniziranog proizvoda inkubirano je 180 minuta pri sobnoj temperaturi s 50 pM 125J-jodtirosil-kalcitonin-genu srodnog peptida (Amersham) i s rastućim koncentracijama ispitnih tvari u ukupnom volumenu od 250 jal. Inkubacija je završena brzom filtracijom kroz GF/B filtere od staklenih vlakana obrađene s polietileniminom (0,1%) upotrebom naprave za skupljanje stanica. Radioaktivnost vezana proteinom izmjerena je pomoću gama brojača. Ne-specifično vezanje je definirano kao vezana radioaktivnost u prisutnosti l |JM humanog CGRP-alfa tijekom inkubacije. After thawing, the homogenized product was diluted 1:10 with assay buffer (50 mM Tris, 150 mM NaCl, 5 mM MgCl2, 1 mM EDTA, pH 7.40) and homogenized for 30 seconds in an Ultra-Turrax. 230 μl of the homogenized product was incubated for 180 minutes at room temperature with 50 pM 125J-iodotyrosyl-calcitonin-gene-related peptide (Amersham) and with increasing concentrations of test substances in a total volume of 250 µl. Incubation was terminated by rapid filtration through GF/B glass fiber filters treated with polyethyleneimine (0.1%) using a cell harvester. Protein-bound radioactivity was measured using a gamma counter. Non-specific binding was defined as bound radioactivity in the presence of 1 µM human CGRP-alpha during incubation.
Krivulje koncentracije vezanja su analizirane usporedbom s ne-linearnom krivuljom pomoću računala. Binding concentration curves were analyzed by comparison with a non-linear curve using a computer.
U opisanom ispitivanju, spojevi opće formule I pokazuju vrijednosti IC50 <10000 nM. In the described test, the compounds of general formula I show IC50 values <10000 nM.
B. CGRP antagonizam- u stanicama SK-N-MC B. CGRP antagonism- in SK-N-MC cells
SK-N-MC stanice (1 milijun stanica) su isprane dva puta s 250 μl pufera za inkubaciju (Hanksov HEPES, 1 mM 3-izobutil-1-metilksantin, 1% BSA, pH 7,4) i prethodno su inkubirane 15 minuta pri 37°C. Nakon dodatka CGRP (10 μl) kao agonista u rastućim koncentracijama (10-11 do 10-6 M), ili dodatka tvari u 3 do 4 različite koncentracije, smjesa je inkubirana još 15 minuta. SK-N-MC cells (1 million cells) were washed twice with 250 μl of incubation buffer (Hanks' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4) and pre-incubated for 15 minutes at 37°C. After the addition of CGRP (10 μl) as an agonist in increasing concentrations (10-11 to 10-6 M), or the addition of the substance in 3 to 4 different concentrations, the mixture was incubated for another 15 minutes.
Zatim je intracelularni cAMP ekstrahiran dodatkom 20 μl 1M HCl i centrifugiran (2000 x g, 4°C, 15 minuta). Intracellular cAMP was then extracted by adding 20 μl of 1M HCl and centrifuged (2000 x g, 4°C, 15 minutes).
Supernatanti su smrznuti u tekućem dušiku i pohranjeni pri -20°C. Supernatants were frozen in liquid nitrogen and stored at -20°C.
Sadržaji cAMP-a u uzorcima određeni su radioimunosnim ispitivanjem (Messrs. Amersham) i vrijednsoti pA2 za antagonističke djelovanje tvari su utvrđene grafički. The contents of cAMP in the samples were determined by radioimmunoassay (Messrs. Amersham) and the pA2 values for the antagonistic effects of the substances were determined graphically.
Spojevi opće formule I pokazuju CGRP-antagonistička svojstva u opisanom modelu ispitivanja in vitro u rasponu doziranja od 10-11 do 10-5 M. The compounds of general formula I show CGRP-antagonistic properties in the described in vitro test model in the dosage range from 10-11 to 10-5 M.
Imajući u vidu njihova farmakološka svojstva, spojevi opće formule I i njihove soli s fiziološki prihvatljivim kiselinama ili bazama su, dakle, prikladni za akutno i profilaktičko liječenje glavobolja, posebno migrena ili cluster glavobolja. Osim toga, spojevi opće formule I također imaju pozitivan učinak na slijedeće bolesti: dijabetes melitus koji ne ovisi o inzulinu ("NIDDM"), kardiovaskularne bolesti, tolerancija morfina, kožne bolesti, posebno toplinom i zračenjem uzrokovane ozljede kože koje uključuju i opekotine od sunca, upalne bolesti, npr. upalne bolesti zglobova (artritis), upalne "plućne bolesti, alergijski rinitis, astmu, bolesti koje prate prekomjernu- vazodilataciju i zbog toga smanjenu cirkulaciju krvi kroz tkivo, npr. šok i sepsa. Sa CGRP-antagonistima predložene prijave povoljno se utječe na simptome nagle vrućine kod žena s nedostatkom estrogena u menopauzi uzrokovane vazodilatacijom i porastom protoka krvi u preventivnim i mogućim akutnim terapijama, pri čemu se ovaj terapeutski pristup razlikuje od nadomjestaka hormona time što nema sporednih učinaka. Osim toga, spojevi opće formule I imaju ublažujući učinak na bol općenito. Bearing in mind their pharmacological properties, the compounds of general formula I and their salts with physiologically acceptable acids or bases are therefore suitable for acute and prophylactic treatment of headaches, especially migraine or cluster headaches. In addition, the compounds of general formula I also have a positive effect on the following diseases: non-insulin-dependent diabetes mellitus ("NIDDM"), cardiovascular diseases, morphine tolerance, skin diseases, especially heat and radiation-induced skin injuries including sunburn , inflammatory diseases, e.g. inflammatory diseases of the joints (arthritis), inflammatory lung diseases, allergic rhinitis, asthma, diseases accompanied by excessive vasodilatation and therefore reduced blood circulation through the tissue, e.g. shock and sepsis. With CGRP-antagonists, proposed applications hot flashes in estrogen-deficient menopausal women are favorably affected by vasodilation and increased blood flow in preventive and possible acute therapies, this therapeutic approach differs from hormone replacement in that it has no side effects. In addition, compounds of general formula I have a mitigating effect on pain in general.
Doziranje potrebno za postizanje odgovarajućeg učinka je uobičajeno 0,001 do 30 mg/kg tjelesne težine, ponajprije 0,01 do 5 mg/kg tjelesne težine kad se daje intravenski ili supkutano i 0,01 do 50 mg/kg tjelesne težine, ponajprije 0,1 do 30 mg/kg tjelesne težine kad se daje oralno, nazalno ili inhalacijom, u svakom slučaju 1 do 3 x dnevno. The dosage required to achieve an adequate effect is usually 0.001 to 30 mg/kg body weight, preferably 0.01 to 5 mg/kg body weight when administered intravenously or subcutaneously and 0.01 to 50 mg/kg body weight, preferably 0.1 up to 30 mg/kg of body weight when administered orally, nasally or by inhalation, in any case 1 to 3 times a day.
U tu svrhu, spojevi opće formule I proizvedeni prema izumu, kombiniraju se prema potrebi s drugim aktivnim tvarima kao što su npr. antiemetici, prokinetici, neuroleptici, antidepresanti, neurokinin antagonisti, anti-konvulzanti, histamine-Hl receptor antagonisti, anti-muskarinici, β-blokeri, α-agonisti i α-antagonisti, ergot alkaloidi, blagi analgetici, ne-steroidna protu-upalna sredstva, kortikosteroidi, antagonisti kalcija, 5-HT1D agonisti ili druga sredstva protiv migrene, zajedno s jednim ili više inertnih konvencionalnih nosača i/ili sredstava za razrjeđivanje, kao što je npr. kukuruzni škrob, laktoza, glukoza, mikrokristalinična celuloza, magnezijev stearat, polivinil pirolidon, limunska kiselina, vinska kiselina, voda, voda/etanol, voda/glicerol, voda/sorbitol, voda/polietilenglikol, propilenglikol, cetilstearil alkohol, karboksimetilceluloza ili masne tvari kao što je tvrda mast ili njihove prikladne mješavine, mogu se formulirati u konvencionalne galenske pripravke kao što su ravne ili prevučene tablete, kapsule, puderi, suspenzije, otopine, odmjerne doze aerosola ili čepići. For this purpose, the compounds of the general formula I produced according to the invention are combined as necessary with other active substances such as, for example, antiemetics, prokinetics, neuroleptics, antidepressants, neurokinin antagonists, anticonvulsants, histamine-H1 receptor antagonists, antimuscarinics, β-blockers, α-agonists and α-antagonists, ergot alkaloids, mild analgesics, non-steroidal anti-inflammatory agents, corticosteroids, calcium antagonists, 5-HT1D agonists or other antimigraine agents, together with one or more inert conventional carriers and / or diluents, such as corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol , propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as tallow or suitable mixtures thereof, may be formulated into conventional galenic preparations such as flat or coated tablets, capsules, powders, suspensions, solutions, metered dose aerosols or suppositories.
Aktivne tvari koje se mogu upotrijebiti za gore spomenute kombinacije uključuju tako, na primjer, meloksikam, ergotamin, dihidroergotamin, metoklopramid, domperidon, difenhidramin, ciklizin, prometazin, klorpromazin, deksametazon, flunarizin, dekstro-propoksifen, meperidin, propranolol, nadolol, atenolol, klonidin, indoramin, karbamazepin, fenitoin, valproat, amitriptilin, lidokain, diltiazem ili sumatriptan i druge 5-HT1D-agoniste kao što su, na primjer, naratriptan, zolmitriptan, avitriptan, rizatriptan i eletriptan. Doziranje ovih aktivnih tvari je svrhovito jednako 1/5 najniže preporučene doze do 1/1 od normalno preporučene doze, tj. na primjer 20 do 100 mg sumatriptana. Active substances that can be used for the aforementioned combinations include, for example, meloxicam, ergotamine, dihydroergotamine, metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine, chlorpromazine, dexamethasone, flunarizine, dextro-propoxyphene, meperidine, propranolol, nadolol, atenolol, clonidine, indoramine, carbamazepine, phenytoin, valproate, amitriptyline, lidocaine, diltiazem or sumatriptan and other 5-HT1D-agonists such as, for example, naratriptan, zolmitriptan, avitriptan, rizatriptan and eletriptan. The dosage of these active substances is expediently equal to 1/5 of the lowest recommended dose to 1/1 of the normally recommended dose, i.e. for example 20 to 100 mg of sumatriptan.
Izum se nadalje odnosi na upotrebu spojeva opće formule I kao dragocjenih pomoćnih sredstava za proizvodnju i čišćenje (afinitetnom kromatografijom) antitijela, kao također i, nakon odgovarajućeg radioaktivnog obilježavanja, za, na primjer, izravno obilježavanje prikladnog predkurzora s 125J ili 131J ili tricijacijom, na primjer zamjenom halogenih atoma s tricijem, u RIA i ELISA ispitivanjima, i kao diagnostičkog ili analitičkog pomoćnog sredstva u istraživanju neurotransmitera. The invention further relates to the use of compounds of the general formula I as valuable auxiliaries for the production and purification (by affinity chromatography) of antibodies, as well as, after appropriate radiolabelling, for example direct labeling of a suitable precursor with 125J or 131J or tritiation, on for example by replacing halogen atoms with tritium, in RIA and ELISA assays, and as a diagnostic or analytical aid in neurotransmitter research.
Primjeri koji slijede predviđeni su za prikaz izuma. The following examples are intended to illustrate the invention.
Prethodne napomene Previous notes
Za sve spojeve dobivene su zadovoljavajuće elementarne analize, IR, UV, 1H-NMR i općenito također i maseni spektri. Ako nije navedeno drugačije, Rf vrijednosti su dobivene upotrebom gotovih pločica silika gela TLC 60 F254 (E. Merck, Darmstadt, proizvod br. 1.05714) bez zasićenja u komori. Ako nije data detaljna informacija o konfiguraciji, tada nije jasno da li se radi o čistom enantiomeru ili je došlo do djelomične ili čak potpune racemizacije. Za ispiranje u kromatografiji upotrijebljena su slijedeća sredstva: Satisfactory elemental analyses, IR, UV, 1H-NMR and generally also mass spectra were obtained for all compounds. Unless stated otherwise, Rf values were obtained using ready-made TLC 60 F254 silica gel plates (E. Merck, Darmstadt, product no. 1.05714) without chamber saturation. If no detailed configuration information is given, then it is not clear whether it is a pure enantiomer or whether partial or even complete racemization has occurred. The following agents were used for washing in chromatography:
El A = etil acetat/metanol 100/5 v/v El A = ethyl acetate/methanol 100/5 v/v
El B = etil acetat/metanol 80/20 v/v El B = ethyl acetate/methanol 80/20 v/v
El C = etil acetat/metanol/konc. amonijak 80/20/1 v/v/v El C = ethyl acetate/methanol/conc. ammonia 80/20/1 v/v/v
El D = diklormetan/cikloheksan/metanol/konc. Amonijak 70/15/15/2 v/v/v/v El D = dichloromethane/cyclohexane/methanol/conc. Ammonia 70/15/15/2 v/v/v/v
El E = etil acetat/ledena octena kiselina 99/1 v/v El E = ethyl acetate/glacial acetic acid 99/1 v/v
El F = etil acetat/metanol/ledena octena kiselina 90/10/1 v/v/v El F = ethyl acetate/methanol/glacial acetic acid 90/10/1 v/v/v
El G = diklormetan/metanol/konc. amonijak 90/10/1 v/v/v El G = dichloromethane/methanol/conc. ammonia 90/10/1 v/v/v
El H = petrol eter/etil acetat 1/1 v/v El H = petroleum ether/ethyl acetate 1/1 v/v
El I = diklormetan/metanol/ledena octena kiselina 90/10/1,5 v/v/v El I = dichloromethane/methanol/glacial acetic acid 90/10/1.5 v/v/v
El K = diklormetan/izopropanol 9/1 v/v E1l = etil acetat/metanol 9/1 v/v El K = dichloromethane/isopropanol 9/1 v/v E1l = ethyl acetate/methanol 9/1 v/v
El M = diklormetan/metanol/konc. amonijak 75/25/0,5 v/v/v El M = dichloromethane/methanol/conc. ammonia 75/25/0.5 v/v/v
El N = diklormetan/etil acetat 1/1 v/v El N = dichloromethane/ethyl acetate 1/1 v/v
El O = diklormetan/metanol 95/5 v/v El O = dichloromethane/methanol 95/5 v/v
El P = diklormetan/etil acetat/cikloheksan/metanol/konc. amonijak 60/16/5/5/0,6 v/v/v/v/v El P = dichloromethane/ethyl acetate/cyclohexane/methanol/conc. ammonia 60/16/5/5/0.6 v/v/v/v/v
U opisu pokusa upotrijebljene su slijedeće kratice: The following abbreviations are used in the description of the experiment:
Mp.: talište (tal.) Mp.: melting point (Italian)
(D) : (raspadanje) (D) : (decay)
DIEA: N,N-diizopropil-etilamin DIEA: N,N-diisopropyl-ethylamine
Boe: (1,1-dimetiletoksi)karbonil Boe: (1,1-dimethylethoxy)carbonyl
TBTU: 2-(1H-benzotriazol-1-il)-1,1,3,3-tetrametil-uronijev tetrafluorborat TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate
HOBt: 1-hidroksibenzotriazol hidrat HOBt: 1-hydroxybenzotriazole hydrate
CDT: 1,1'-karbonildi-(1,2,4-triazol) CDT: 1,1'-carbonyldi-(1,2,4-triazole)
THF: tetrahidrofuran THF: tetrahydrofuran
DMF: dimetilformamid DMF: dimethylformamide
EE: etil acetat EE: ethyl acetate
PE: petrol eter PE: petroleum ether
LM: otapala LM: solvents
I. No.: Item number (spoj broj) I. No.: Item number
U nastavku su zbirno prikazana značenja simbola koji se sastoje od slova i brojeva koji su upotrijebljeni u primjerima: Below is a summary of the meanings of the symbols consisting of letters and numbers used in the examples:
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A. Priprava intermedijarnih spojeva A. Preparation of intermediate compounds
Primjer A1 Example A1
cis-2-(4-klorbenzoil)-ciklopropankarboksilna kiselina cis-2-(4-chlorobenzoyl)-cyclopropanecarboxylic acid
4,5 g (0,040 mola) klorbenzena i 5, O g (0,0446 mola) anhidrida 1,2-ciklopropandikarboksilne kiseline uzastopce se doda kap po kap k mješavini od 60,0 g (0,45 mola) bezvodnog aluminijevog klorida i 9 ml (0,115 mola) bezvodnog dimetilformamida uz održavanje reakcijske temperature od 60 do 70°C i zatim se smjesu drži 1 sat pri 70°C. Kad se ohladi, reakcijsku smjesu se umiješa u mješavinu od 500 g smrvljenog leda i 60 ml konc. solne kiseline, talog se odsisa, ispere temeljito s vodom i osuši preko Siccapenta u vakuumskoj komori za sušenje pri temperaturi od 50°C. Dobije se 7,8 g (87% od teorijskog) bezbojnih kristala, talište 150-153°C. 4.5 g (0.040 mol) of chlorobenzene and 5.0 g (0.0446 mol) of 1,2-cyclopropanedicarboxylic acid anhydride were successively added dropwise to a mixture of 60.0 g (0.45 mol) of anhydrous aluminum chloride and 9 ml (0.115 mol) of anhydrous dimethylformamide while maintaining the reaction temperature from 60 to 70°C and then the mixture is kept for 1 hour at 70°C. When it cools down, the reaction mixture is mixed into a mixture of 500 g of crushed ice and 60 ml of conc. hydrochloric acid, the precipitate is suctioned off, washed thoroughly with water and dried over Siccapent in a vacuum drying chamber at a temperature of 50°C. 7.8 g (87% of theoretical) of colorless crystals are obtained, melting point 150-153°C.
Primjer A2 Example A2
trans-2-(4-amino-3,5-dibrombenzoil)-ciklopropankarboksilna kiselina trans-2-(4-amino-3,5-dibromobenzoyl)-cyclopropanecarboxylic acid
Proizvedena je analogno primjeru 2 iz metil trans-2-(4-amino-3,5-dibrombenzoil)-ciklopropankarboksilata saponifikacijom s hidratom litijevog hidroksida u mješavini vode i tetrahidrofurana (2/3 v/v), s iskorištenjem od 76% od teorijskog. Bezbojni kristali. It was produced analogously to example 2 from methyl trans-2-(4-amino-3,5-dibromobenzoyl)-cyclopropanecarboxylate by saponification with lithium hydroxide hydrate in a mixture of water and tetrahydrofuran (2/3 v/v), with a recovery of 76% of the theoretical . Colorless crystals.
IR (KBr) : 3473,2, 3345,9 (NH2); 1714,4 (C-O) cm-1. IR (KBr): 3473.2, 3345.9 (NH2); 1714.4 (C-O) cm-1.
Primjer A3 Example A3
Metil trans-2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karboksilat Methyl trans-2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carboxylate
0,45 g (0,01781 mola) 95%-tnog natrijevog hidrida doda se u malim količinama u otopinu od 3,9 g (0,02074 mola) trimetil-oksosulfonijevog jodida u 50 ml bezvodnog dimetil-sulfoksida pri sobnoj temperaturi uz miješanje. Smjesu se miješa još 30 minuta pri sobnoj temperaturi i zatim se kap po kap doda otopinu od 5,8 g (0,01598 mola) metil trans-4-(4-amino-3,5-dibromfenil)-4-okso-butenoata u 50 ml dimetilsulfoksida bez vanjskog grijanja, nakon čega se temperaturu smjese povisi na 35°C i miješanje se nastavi još jedan sat pri sobnoj temperaturi. Smjesu se promiješa u 500 ml zasićene vodene otopine soli, zatim se temeljito ekstrahira s etil acetatom. Sjedinjeni ekstrakti u etil acetatu se osuše preko natrijevog sulfata i ispare u vakuumu. Iz ostatka se, nakon čišćenja kromatografijom na stupcu silika gela (30 do 60 μm) upotrebom EE/cikloheksana (1/1 v/v) za ispiranje, dobije 2,6 g (43% od teorijskog) bezbojnog ulja. 0.45 g (0.01781 mol) of 95% sodium hydride is added in small amounts to a solution of 3.9 g (0.02074 mol) of trimethyloxosulfonium iodide in 50 ml of anhydrous dimethyl sulfoxide at room temperature with stirring . The mixture was stirred for another 30 minutes at room temperature and then a solution of 5.8 g (0.01598 mol) of methyl trans-4-(4-amino-3,5-dibromophenyl)-4-oxo-butenoate was added dropwise. in 50 ml of dimethylsulfoxide without external heating, after which the temperature of the mixture is raised to 35°C and the mixing is continued for another hour at room temperature. The mixture is stirred in 500 ml of saturated aqueous salt solution, then thoroughly extracted with ethyl acetate. The combined extracts in ethyl acetate were dried over sodium sulfate and evaporated in vacuo. From the residue, after purification by chromatography on a silica gel column (30 to 60 μm) using EE/cyclohexane (1/1 v/v) for elution, 2.6 g (43% of theory) of a colorless oil is obtained.
IR (KBr) : 3475, 3363 (NH2); 1728, 1662 (C=O) cm-1 IR (KBr): 3475, 3363 (NH2); 1728, 1662 (C=O) cm-1
MS: M+ = 375/377/379 (Br2) MS: M+ = 375/377/379 (Br2)
Primjer A4 Example A4
Metil trans-4-(4-amino-3, 5-dibromfenil)-4-okso-butenoat Methyl trans-4-(4-amino-3, 5-dibromophenyl)-4-oxo-butenoate
Smjesu od 5,6 g (0,016 mola) trans-4-(4-amino-3,5-dibromfenil)-4-okso-butenske kiseline, 50- ml bezvodnog metanola i 4,0 g (0,0368 mola) trimetilklorsilana miješa se 3 dana pri sobnoj temperaturi. Otapalo se odstrani u vakuumu, ostatak se podijeli između etil acetata i 10%-tne otopine natrijevog hidrogen karbonata. Organske faze se osuše preko natrijevog sulfata i ispare još jednom u vakuumu, čime se dobije 5,8 g (100% od teorijskog) bezbojnog ulja koje se upotrebljava bez ikakvog daljnjeg čišćenja. A mixture of 5.6 g (0.016 mol) of trans-4-(4-amino-3,5-dibromophenyl)-4-oxo-butenoic acid, 50 ml of anhydrous methanol and 4.0 g (0.0368 mol) of trimethylchlorosilane it is mixed for 3 days at room temperature. The solvent was removed in vacuo, the residue was partitioned between ethyl acetate and 10% sodium hydrogen carbonate solution. The organic phases were dried over sodium sulfate and evaporated once more in vacuo to give 5.8 g (100% of theory) of a colorless oil which was used without any further purification.
MS: M+ = 361/363/365 (Br2) MS: M+ = 361/363/365 (Br2)
Primjer A5 Example A5
3,4-dihidro-6-[2-(dimetilamino) etoksi]-3-(4-piperidinil)-2(1H)-kinazolinon 3,4-dihydro-6-[2-(dimethylamino)ethoxy]-3-(4-piperidinyl)-2(1H)-quinazolinone
Smjesu od 0,9 g (0,0022 mola) 3,4-dihidro-6-[2-(dimetil-amino)etoksi]-3-(1-fenilmetil-4-piperidinil)-2(1H)-kinazolinona, 10 ml metanola i 0,5 g paladij(II) hidroksida (Pearlmanov katalizator) hidrogenira se do prestanka uzimanja vodika. Katalizator se odfiltrira, filtrat se ispari u vakuumu i dobiveni ostatak se upotrebljava u slijedećem stupnju bez ikakvog daljnjeg čišćenja. Iskorištenje: 0,6 g (86% od teorijskog). A mixture of 0.9 g (0.0022 mol) of 3,4-dihydro-6-[2-(dimethyl-amino)ethoxy]-3-(1-phenylmethyl-4-piperidinyl)-2(1H)-quinazolinone, 10 ml of methanol and 0.5 g of palladium(II) hydroxide (Pearlman's catalyst) are hydrogenated until hydrogen absorption stops. The catalyst is filtered off, the filtrate is evaporated in vacuo and the resulting residue is used in the next step without any further purification. Yield: 0.6 g (86% of theoretical).
IR (KBr) : 1662 (C=O) cm-1 IR (KBr): 1662 (C=O) cm-1
MS: M+ = 318 MS: M+ = 318
Analogno su dobiveni slijedeći spojevi: Analogously, the following compounds were obtained:
[image] [image]
Primjer A6 Example A6
3,4-dihidro-6-(4-metil-1-piperazinil)-3-(4-piperidinil)-2(1H)-kinazolinan 3,4-dihydro-6-(4-methyl-1-piperazinyl)-3-(4-piperidinyl)-2(1H)-quinazolinane
2 ml trifluoroctene kiseline doda se u ledeno hladnu otopinu od 1,1 g (2,561 mmola) 3,4-dihidro-3-[1-(1,1-dimetiletoksikarbonil)-4-piperidinil]-6-(4-metil-1-piperazinil) -2(1H)-kinazolinona u 20 ml metilen klorida. Reakcijsku smjesu se miješa 15 sati pri sobnoj temperaturi i 5 sati pri 40°C i zatim se ispari do kraja u vakuumu. Dobiveni ostatak se uzme u 5 ml vode, nastalu otopinu se zasiti s kalijevim karbonatom i iscrpno ekstrahira s diklormetanom. Sjedinjeni ekstrakti se ispare do suhog u vakuumu. Dobiveni ostatak se očisti kromatografijom na stupcu silika gela najprije upotrebom diklormetan/metanola 9/1 (v/v), a zatim diklormetan/metanol/konc. amonijaka 70/30/3 (v/v/v) za ispiranje. Odgovarajuće frakcije se ispare do kraja u vakuumu, dobiveni ostatak (0,5 g; 59% od teorijskog) se upotrebljava u slijedećem stupnju bez daljnjeg čišćenja. 2 ml of trifluoroacetic acid was added to an ice-cold solution of 1.1 g (2.561 mmol) of 3,4-dihydro-3-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-6-(4-methyl- 1-piperazinyl)-2(1H)-quinazolinone in 20 ml of methylene chloride. The reaction mixture was stirred for 15 hours at room temperature and 5 hours at 40°C and then completely evaporated in a vacuum. The obtained residue is taken in 5 ml of water, the resulting solution is saturated with potassium carbonate and exhaustively extracted with dichloromethane. The combined extracts are evaporated to dryness in vacuo. The obtained residue is purified by chromatography on a silica gel column, first using dichloromethane/methanol 9/1 (v/v), and then dichloromethane/methanol/conc. of ammonia 70/30/3 (v/v/v) for rinsing. The corresponding fractions were evaporated to completion in vacuo, the resulting residue (0.5 g; 59% of theory) was used in the next step without further purification.
Primjer A7 Example A7
3,4-dihidro-6-[(1,3-dioksolan-2-il)metoksi]-3-(1-fenil-metil-4-piperidinil)-2(1H)-kinazolinon 3,4-dihydro-6-[(1,3-dioxolan-2-yl)methoxy]-3-(1-phenyl-methyl-4-piperidinyl)-2(1H)-quinazolinone
0,36 g (14,25 ramola) 95%-tnog natrijevog hidrida doda se u obrocima uz miješanje k otopini od 5,0 g (14,82 mmolova) 3,4-dihidro-6-hidroksi-3-(1-fenilmetil-4-piperidinil)-2(1H)-kinazolinona u 120 ml bezvodnog dimetil-formamida pri sobnoj temperaturi i smjesu se zatim drži 15 minuta pri 50°C. Nastane gusta bezbojna kaša. Nakon dodatka 5,0 g (37,04 mmolova) 2-(brom-metil)-1,3-di-oksolana, smjesu se grije 90 minuta pri 90°C. Kad se ohladi, smjesu se umiješa u zasićenu vodenu otopinu soli i iscrpno se ekstrahira s etil acetatom. Sjedinjeni ekstrati se osuše preko natrijevog sulfata i ispare do suhog u vakuumu. Dobiveni ostatak se očisti _kromatografijom na stupcu silika gela (30-60 (im) upotrebom diklormetan/EE/cikloheksan/metanol/konc. amonijaka 60/16/5/5/0,6 v/v/v/v/v za ispiranje. Obradom odgovarajućih frakcija dobije se 2,5 g (41% od teorijskog) bezbojnog ulja, Rf = 0,47 (diklor-metan/EE/cikloheksan/metanol/konc. amonijak 60/16/5/5/0,6 v/v/v/v/v). 0.36 g (14.25 mmol) of 95% sodium hydride was added portionwise with stirring to a solution of 5.0 g (14.82 mmol) of 3,4-dihydro-6-hydroxy-3-(1- phenylmethyl-4-piperidinyl)-2(1H)-quinazolinone in 120 ml of anhydrous dimethylformamide at room temperature and the mixture is then kept for 15 minutes at 50°C. A thick colorless slurry is formed. After the addition of 5.0 g (37.04 mmol) of 2-(bromomethyl)-1,3-dioxolane, the mixture is heated for 90 minutes at 90°C. When cooled, the mixture was stirred into saturated aqueous salt solution and exhaustively extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated to dryness in vacuo. The resulting residue is purified by _chromatography on a silica gel column (30-60 (im) using dichloromethane/EE/cyclohexane/methanol/conc. ammonia 60/16/5/5/0.6 v/v/v/v/v for washing Processing of the appropriate fractions yields 2.5 g (41% of theory) of a colorless oil, Rf = 0.47 (dichloromethane/EE/cyclohexane/methanol/conc. ammonia 60/16/5/5/0.6 v /v/v/v/v).
IR (KBr) : 1662 (C=O) cm-1 IR (KBr): 1662 (C=O) cm-1
Analogno su dobiveni slijedeći spojevi: Analogously, the following compounds were obtained:
[image] [image]
Primjer A8 Example A8
3,4-dihidro-6-[2-(dimetilamino)etoksi]-3-(1-fenilmetil-4-piperidinil)-2(1H)-kinazolinon 3,4-dihydro-6-[2-(dimethylamino)ethoxy]-3-(1-phenylmethyl-4-piperidinyl)-2(1H)-quinazolinone
Smjesu od 1,1 g (3,26 mmola) 3,4-dihidro-6-hidroksi-3-(1-fenilmetil-4-piperidinil)-2(1H)-kinazolinona, 50 ml tetrahidrofurana, 0,30 g (3,366 mmola) 2-dimetil-amino-etanola, 0,94 g (3,584 mmola) trifenilfosfina i 0,56 g (3,216 mmola) estera azodikarboksilne kiseline miješa se jedan sat pri sobnoj temperaturi, 6 sati pod refluksom i još 13 sati pri sobnoj temperaturi. Otapalo se odstrani u vakuumu i ostatak se očisti kromatografijom na stupcu silika gela (30-60 μm) upotrebom diklormetan/EE/ciklo-heksan/metanol/konc. amonijaka 60/16/5/5/0,6 v/v/v/v/v za Ispiranje. Obradom odgovarajućih frakcija dobije se 0,9 g (69% od teorijskog) bezbojne kristalinične tvari, Rf = 0,47 (diklormetan/EE/cikloheksan/metanol/konc. amonijak 6G-/16/5/5/0, 6 v/v/v/v/v). A mixture of 1.1 g (3.26 mmol) of 3,4-dihydro-6-hydroxy-3-(1-phenylmethyl-4-piperidinyl)-2(1H)-quinazolinone, 50 ml of tetrahydrofuran, 0.30 g ( 3.366 mmol) of 2-dimethyl-amino-ethanol, 0.94 g (3.584 mmol) of triphenylphosphine and 0.56 g (3.216 mmol) of azodicarboxylic acid ester are mixed for one hour at room temperature, 6 hours under reflux and another 13 hours at room temperature. temperature. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (30-60 μm) using dichloromethane/EE/cyclohexane/methanol/conc. of ammonia 60/16/5/5/0.6 v/v/v/v/v for rinsing. Treatment of the appropriate fractions yields 0.9 g (69% of theory) of a colorless crystalline substance, Rf = 0.47 (dichloromethane/EE/cyclohexane/methanol/conc. ammonia 6G-/16/5/5/0, 6 v/ v/v/v/v).
MS: ESI: (M+H) * = 409; (M+2H)++ = 205; (M+Na)+ = 431 MS: ESI: (M+H) * = 409; (M+2H)++ = 205; (M+Na)+ = 431
Analogno su dobiveni slijedeći spojevi: Analogously, the following compounds were obtained:
[image] [image]
Primjer A9 Example A9
3,4-dihidro-3-[l-(l,1-dimetiletoksikarbonil)-4-piperidinil]-6-(4-metil-1-piperazinil)-2(1H)-kinazolinon 3,4-dihydro-3-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-6-(4-methyl-1-piperazinyl)-2(1H)-quinazolinone
Smjesu od 10,0 g (24,372 mmola) 6-brom-3,4-dihidro-3-[1-(1,1-dimetiletoksikarbonil)-4-piperidinil]-2(1H)-kinazolinona, 2,5 g (24,96 mola) 1-metilpiperazina, 4,81 g (50,05 mmolova) natrijevog terc-butoksida, 285 mg (0,4766 mmola) bis-(dibenzilidenaceton)-paladija, 305 mg (1,002 mmola) tris-(o-tolil)-fosfina i 100 ml toluena refluktira se 14 sati. Nakon dodatka još jednom jednake količine 1-metil-piperazina, natrijevog terc-butoksida, bis-(dibenziliden-aceton)-paladija i tris-(o-tolil)-fosfina, smjesu se refluktira još 48 sati. Zatim se smjesu filtrira kroz aktivirani ugljen i filtrat se ispari do suhog u vakuumu. Ostatak se podijeli između diklormetana i vode. Organske faze se ekstrahiraju dva puta s razrijeđenom vodenom otopinom limunske kiseline. Tako dobiveni kiseli ekstrakti se zaluže s natrijevim hidroksidom i ekstrahiraju iscrpno s diklormetanom. Sjedinjeni ekstrakti u diklor-metanu se ispare do suhog u vakuumu, ostatak se očisti kromatografijom na stupcu silika gela (30-60 μm) upotrebom najprije diklormetana, a zatim metanol/konc. amonijaka 9/1 v/v za ispiranje. Nakon uobičajene obrade odgovarajućih eluata dobije se 1,1 g (11% od teorijskog) bezbojne tvari. A mixture of 10.0 g (24.372 mmol) of 6-bromo-3,4-dihydro-3-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-2(1H)-quinazolinone, 2.5 g ( 24.96 mol) 1-methylpiperazine, 4.81 g (50.05 mmol) sodium tert-butoxide, 285 mg (0.4766 mmol) bis-(dibenzylideneacetone)-palladium, 305 mg (1.002 mmol) tris-(o -tolyl)-phosphine and 100 ml of toluene is refluxed for 14 hours. After adding an equal amount of 1-methyl-piperazine, sodium tert-butoxide, bis-(dibenzylidene-acetone)-palladium and tris-(o-tolyl)-phosphine, the mixture is refluxed for another 48 hours. The mixture is then filtered through activated carbon and the filtrate is evaporated to dryness under vacuum. The residue was partitioned between dichloromethane and water. The organic phases are extracted twice with dilute aqueous citric acid. The acid extracts thus obtained are made alkaline with sodium hydroxide and extracted exhaustively with dichloromethane. The combined extracts in dichloromethane are evaporated to dryness in vacuo, the residue is purified by chromatography on a silica gel column (30-60 μm) using first dichloromethane and then methanol/conc. of ammonia 9/1 v/v for rinsing. After the usual treatment of the respective eluates, 1.1 g (11% of the theoretical) of a colorless substance is obtained.
IR (KBr) : 1670 (C=O cm-1 IR (KBr): 1670 (C=O cm-1
M+ = 429 M+ = 429
Primjer A10 Example A10
3,4-dihidro-7-hidroksi-3-(1-fenilmetil-4-piperidinil)-2(1H)-kinazolinon 3,4-dihydro-7-hydroxy-3-(1-phenylmethyl-4-piperidinyl)-2(1H)-quinazolinone
Smjesu od 18,0 g (0,0512 mola) 3,4-dihidro-7-metoksi-3-(1-fenilmetil-4-piperidinil)-2(1H)-kinazolinona i 100 g piridin hidroklorida grije se 3 sata pri 160°C uz miješanje. Kad se ohladi, proizvod se otopi u 500 ml vode, dobivenu otopinu se oprezno pomiješa sa suviškom krutog natrijevog hidrogen karbonata, nakon čega se istaloži ulje visoke viskoznosti. To ulje se preuzme u 150 ml metanola, nastalu metanolnu otopinu se izbistri preko aktiviranog ugljena i zatim se otapalo odstrani još jednom u vakuumu. Ostatak se pomiješa s 50 ml acetonitrila i zatim se zakuha. Pusti se ohladiti i nastali talog se odsisa i osuši u vakuumu pri sobnoj temperaturi. Iskorištenje: 10,8 g (63% od teorijskog). A mixture of 18.0 g (0.0512 mol) of 3,4-dihydro-7-methoxy-3-(1-phenylmethyl-4-piperidinyl)-2(1H)-quinazolinone and 100 g of pyridine hydrochloride is heated for 3 hours at 160°C with stirring. When cooled, the product is dissolved in 500 ml of water, the resulting solution is carefully mixed with an excess of solid sodium hydrogen carbonate, after which a high-viscosity oil is precipitated. This oil is taken up in 150 ml of methanol, the resulting methanol solution is clarified over activated carbon and then the solvent is removed once more under vacuum. The residue is mixed with 50 ml of acetonitrile and then boiled. It is allowed to cool and the resulting precipitate is sucked off and dried in a vacuum at room temperature. Yield: 10.8 g (63% of theoretical).
Rf = 0,32 (MP F). Rf = 0.32 (MP F).
IR (KBr) : 1649 (C=O) cm-1 IR (KBr): 1649 (C=O) cm-1
MS: M* = 337 MS: M* = 337
Primjer A11 Example A11
3,4-dihidro-7-metoksi-3-(1-fenilmetil-4-piperidinil)-2(1H)-kinazolinon 3,4-dihydro-7-methoxy-3-(1-phenylmethyl-4-piperidinyl)-2(1H)-quinazolinone
Smjesu od 2,5 g (7,682 mmolova) 2-amino-4-metoksi-N-(1-fenilmetil-4-piperidinil)-benzilamina, 1,62 g (10 mmolova) N,N'-karbonildiimidazola i 25 ml dimetilformamida grije se 2,5 sata pri 90°C uz miješanje. Kad se ohladi, smjesu se promiješa u 100 ml ledene vode, nastalu suspenziju se zasiti s 10 ml terc-butil metil etera, nastali talog se odfiltrira odsisavanjem, ispere s vodom i zatim s terc-butil metil eterom. Nakon sušenja u vakuumu dobije se 1,9 g (70% od teorijskog) bezbojnih kristala. A mixture of 2.5 g (7.682 mmol) of 2-amino-4-methoxy-N-(1-phenylmethyl-4-piperidinyl)-benzylamine, 1.62 g (10 mmol) of N,N'-carbonyldiimidazole and 25 ml of dimethylformamide it is heated for 2.5 hours at 90°C with stirring. When cooled, the mixture is stirred in 100 ml of ice water, the resulting suspension is saturated with 10 ml of tert-butyl methyl ether, the resulting precipitate is filtered off with suction, washed with water and then with tert-butyl methyl ether. After drying in a vacuum, 1.9 g (70% of theoretical) of colorless crystals are obtained.
IR (KBr) : 1664 (C-0) cm-1 IR (KBr): 1664 (C-0) cm-1
MS: M+ = 351 MS: M+ = 351
Primjer A12 Example A12
2-amino-4-metoksi-N-(1-fenilmetil-4-piperidinil)-benzilamin 2-amino-4-methoxy-N-(1-phenylmethyl-4-piperidinyl)-benzylamine
Otopinu od 3,2 g (9,003 ramolova) 4-metoksi-2-nitro-N-(l-fenilmetil-4-piperidinil)-benzilamina u 30 ml metanola hidrogenira se u prisutnosti 1 g 10%-tnog rodija na ugljenu 5 sati pri sobnoj temperaturi. Katalizator se odfiltrira i filtrat se ispari do suhog u vakuumu. Dobije se 2,5 g (85% od teorijskog) bezbojnog ulja visoke viskoznosti, koje se dalje obrađuje bez daljnjeg čišćenja. A solution of 3.2 g (9.003 rammoles) of 4-methoxy-2-nitro-N-(1-phenylmethyl-4-piperidinyl)-benzylamine in 30 ml of methanol is hydrogenated in the presence of 1 g of 10% rhodium on charcoal for 5 hours at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness under vacuum. 2.5 g (85% of theory) of a colorless oil of high viscosity is obtained, which is further processed without further purification.
Rf = 0,34 (MP F). Rf = 0.34 (MP F).
IR (KBr): no C=O IR (KBr): but C=O
MS: M* = 325 MS: M* = 325
Primjer A13 Example A13
4-metoksi-2-nitro-N-(1-fenilmetiI-4-piperidinil)-benzilamin 4-Methoxy-2-nitro-N-(1-phenylmethyl-4-piperidinyl)-benzylamine
Smjesu od 3,0 g (16,561 mmolova) 4-metoksi-2-nitro-benzaldehida, 3,2 g (16,817 mmolova) 1-fenilmetil-4-piperidinamina i 30 ml metanola miješa se 2 sata pri sobnoj temperaturi. Zatim se doda 681 mg (18,0 mmolova) natrijevog borhidrida i miješanje se nastavi još jedan sat pri sobnoj temperaturi. Smjesu se pomiješa u 500 ml ledene vode i oprezno se zakiseli s 10%-tnom solnom kiselinom. Dobivenu otopinu se ispere dva puta s 50 ml terc-butil metil etera, zatim se zaluži s 20%-tnom otopinom natrijevog hidroksida i ekstrahira iscrpno s terc-butil metil eterom. Konačno, dobiveni ekstrakti se sjedine, i«peru se dva puta s 20 ml vode, osuše se preko magnezijevog sulfata i ispare do suhog u vakuumu. Zaostalo bezbojno ulje se upotrebljava u slijedećem stupnju bez ikakvog daljnjeg čišćenja. Iskorištenje: 3,2 g (54% od teoriiskog). A mixture of 3.0 g (16.561 mmol) of 4-methoxy-2-nitro-benzaldehyde, 3.2 g (16.817 mmol) of 1-phenylmethyl-4-piperidinamine and 30 ml of methanol was stirred for 2 hours at room temperature. Then 681 mg (18.0 mmol) of sodium borohydride was added and stirring was continued for another hour at room temperature. The mixture is mixed in 500 ml of ice water and carefully acidified with 10% hydrochloric acid. The resulting solution is washed twice with 50 ml of tert-butyl methyl ether, then made alkaline with a 20% sodium hydroxide solution and extracted exhaustively with tert-butyl methyl ether. Finally, the obtained extracts are combined, washed twice with 20 ml of water, dried over magnesium sulfate and evaporated to dryness under vacuum. The remaining colorless oil is used in the next step without any further cleaning. Yield: 3.2 g (54% of theoretical).
IR (KBr): no C=O IR (KBr): but C=O
MS: M* = 355 MS: M* = 355
B. Priprava krajnjih spojeva B. Preparation of end joints
Primjer 1 Example 1
cis-3-{1-[2-(4-klorbenzoil)-ciklcpropankarbonil]-4-piperidinil)-3,4-dihidro-2 (1H)-kinazolinon (spoj br. 1) cis-3-{1-[2-(4-chlorobenzoyl)-cyclopropanecarbonyl]-4-piperidinyl)-3,4-dihydro-2 (1H)-quinazolinone (compound no. 1)
Smjesu od 1,0 g (4,452 mmola trans-2-(4-klorbenzoil)-ciklopropankarboksilne kiseline, 0,97 g (4,194 mmola) 3,4-dihidro-3-(4-piperidinil)-2(1H)-kinazolinona, 1,4 g (4,36 mmola) TBTU, 0,455 mg (4,5 mmola) trietilamina i 20 ml dimetilformamida miješa se 5 sati pri sobnoj temperaturi. Reakcijsku smjesu se oslobodi od otapala u vakuumu, razrijedi se s 300 ml vode i blago se zakiseli s limunskom kiselinom. Nastali talog se odsisa i oprezno ispere s vodom, zatim s 5 ml tetrahidrofurana i konačno se osuši u sušilici s optočnim zrakom pri temperaturi od 60°C. Dobije se 1,3 g (71% od teorijskog) bezbojnog kristaliničnog proizvoda, talište 272-273°C i Rf 0,24 (MP A). A mixture of 1.0 g (4.452 mmol) trans-2-(4-chlorobenzoyl)-cyclopropanecarboxylic acid, 0.97 g (4.194 mmol) 3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone , 1.4 g (4.36 mmol) of TBTU, 0.455 mg (4.5 mmol) of triethylamine and 20 ml of dimethylformamide were stirred for 5 hours at room temperature. The reaction mixture was freed from the solvent under vacuum, diluted with 300 ml of water and slightly acidified with citric acid. The resulting precipitate is filtered off with suction and carefully washed with water, then with 5 ml of tetrahydrofuran and finally dried in a circulating air dryer at a temperature of 60° C. 1.3 g (71% of theoretical) are obtained colorless crystalline product, melting point 272-273°C and Rf 0.24 (MP A).
IR (KBr) : 1674,1 cm-1 (C=O) MS: IR (KBr) : 1674.1 cm-1 (C=O) MS:
M+ = 437/439 (Cl) M+ = 437/439 (Cl)
Analogno su proizvedeni slijedeći spojevi: Analogously, the following compounds were produced:
[image] [image] [image] [image] [image] [image] [image] [image]
Primjer 2 Example 2
trans-3-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-3,4-dihidro-6-(hidroksikarbonil-metoksi)-2(1H)-kinazolinon (spoj br. 23) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-3,4-dihydro-6-(hydroxycarbonyl-methoxy)-2(1H) -quinazolinone (compound no. 23)
Otopinu od 0,15 g (3,57 mmola) litij hidroksid hidrata u 10 ml vode doda se k otopini od 0,6 g (0,903 mmola) trans-3-{1-[2-(4-amino-3,5-dibrombenzoil)-ciklopropan-karbonil]-4-piperidinil}-3,4-dihidro-6-(metoksikarbonil-metoksi)-2(1H)-kinazolinona (spoj br. 22) u mješavini od 10 ml THF-a i 10 ml metariola. Nakon miješanje 14 sati pri sobnoj temperaturi, organska otapala se izdestiliraju u vakuumu i dobiveni ostatak se pomiješa s 3,6 ml 1N solne kiseline. Nastali talog se odsisa i osuši u vakuumu pri 30°C. Ostatak se preuzme u tetrahidrofuran, nastalu otopinu se vruću profiltrira i kad se ohladi miješa se s diizopropil eterom do završetka reakcije taloženja. Talog se odsisa. Nakon sušenja u sušilici s optočnim zrakom dobije se 0,25 g (43% od teorijskog) bezbojnih kristala. Rf 0,63 (MP C). A solution of 0.15 g (3.57 mmol) of lithium hydroxide hydrate in 10 ml of water is added to a solution of 0.6 g (0.903 mmol) of trans-3-{1-[2-(4-amino-3,5 -dibromobenzoyl)-cyclopropane-carbonyl]-4-piperidinyl}-3,4-dihydro-6-(methoxycarbonyl-methoxy)-2(1H)-quinazolinone (compound no. 22) in a mixture of 10 ml of THF and 10 ml of metariol. After stirring for 14 hours at room temperature, the organic solvents are distilled off in vacuo and the obtained residue is mixed with 3.6 ml of 1N hydrochloric acid. The resulting precipitate is sucked off and dried in a vacuum at 30°C. The residue is taken up in tetrahydrofuran, the resulting solution is filtered while hot, and when it cools, it is mixed with diisopropyl ether until the precipitation reaction is complete. The residue is sucked off. After drying in a dryer with circulating air, 0.25 g (43% of theoretical) of colorless crystals are obtained. Rf 0.63 (MPC).
IR (KBr): 1730 cm1 (C=O) IR (KBr): 1730 cm1 (C=O)
MS: ESI: (M-H+2Na)+ = 693/695/697 (Br2); MS: ESI: (M-H+2Na)+ = 693/695/697 (Br2);
(M-H)- = 647/649/651 (Br2); (M-H)- = 647/649/651 (Br2);
(M+Na)+ = 671/673/675 (Br2) (M+Na)+ = 671/673/675 (Br2)
Analogno su proizvedeni slijedeći spojevi: Analogously, the following compounds were produced:
[image] [image]
Primjeri koji slijede pokazuju pripravu nekih farmaceutskih formulacija koje kao aktivan sastojak sadrže bilo koji željeni spoj opće formule I: The following examples show the preparation of some pharmaceutical formulations which contain as an active ingredient any desired compound of the general formula I:
Primjer I Examples
Kapsule za inhalaciju praha koje sadrže 1 mg aktivnog sastojka Capsules for powder inhalation containing 1 mg of the active ingredient
Sastav: Composition:
1 kapsula inhalaciju praha sadrži: 1 capsule inhalation powder contains:
aktivan sastojak 1,0 mg active ingredient 1.0 mg
laktoza 20,0 mg lactose 20.0 mg
tvrde želatinske kapsule 50,0 mg hard gelatin capsules 50.0 mg
71,0 mg 71.0 mg
Postupak priprave: Preparation process:
Aktivan sastojak se usitni do veličine čestica potrebne za inhalaciju tvari. Usitnjeni aktivan sastojak se homogeno pomiješa s laktozom. Smjesu se prenese u tvrde želatinske kapsule. The active ingredient is pulverized to the particle size required for inhalation of the substance. The crushed active ingredient is homogeneously mixed with lactose. The mixture is transferred into hard gelatin capsules.
Primjer II Example II
Inhalacijaka otopina za Respimat® koja sadrže 1 mg aktivnog sastojka Inhalation solution for Respimat® containing 1 mg of active ingredient
Sastav: Composition:
1 udah sadrži: 1 breath contains:
aktivan sastojak 1,0 mg active ingredient 1.0 mg
benzalkonij klorid 0,002 mg benzalkonium chloride 0.002 mg
dinatrijev edetat 0,0075 mg disodium edetate 0.0075 mg
pročišćena voda ad 15,0 μl purified water ad 15.0 μl
Postupak priprave: Preparation process:
Aktivan sastojak i benzalkonij klorid se otope u vodi i prenesu u umetak za Respimat®. The active ingredient and benzalkonium chloride are dissolved in water and transferred to the Respimat® insert.
Primjer III Example III
Inhalacijska otopina za atomizer koja sadrži l mg aktivnog sastojka Inhalation solution for atomizer containing 1 mg of active ingredient
Sastav: Composition:
1 vijala sadrži: 1 vial contains:
aktivan sastojak 0,1 g active ingredient 0.1 g
natrijev klorid 0,18 g sodium chloride 0.18 g
benzalkonij klorid 0,002 g benzalkonium chloride 0.002 g
pročišćena voda ad 20,0 ml purified water ad 20.0 ml
Postupak priprave: Preparation process:
Aktivan sastojak, natrijev klorid i benzalkonijev kloride se otope u vodi. The active ingredient, sodium chloride and benzalkonium chlorides, dissolve in water.
Primjer IV Example IV
Odmjerni aerosol na potisni plin koji sadrži 1 mg aktivnog sastojka Metered propellant aerosol containing 1 mg of active ingredient
Sastav: Composition:
1 udah sadrži: 1 breath contains:
aktivan sastojak 1,0 mg active ingredient 1.0 mg
lecitin 0,1% lecithin 0.1%
potisni plin ad 50,0 μl propellant gas ad 50.0 μl
Postupak priprave Preparation process
Mikronizirani aktivan sastojak se homogeno suspendira u mješavini lecitina i potisnog plina. Suspenziju se prenese u tlačni spremnik s odmjernim ventilom. The micronized active ingredient is homogeneously suspended in a mixture of lecithin and pressure gas. The suspension is transferred to a pressure tank with a metering valve.
Primjer V Example V
Nazalni sprej koji sadrže l mg aktivnog sastojka Nasal spray containing 1 mg of active ingredient
Sastav: Composition:
aktivan sastojak 1/0 mg active ingredient 1/0 mg
natrijev klorid 0,9 mg sodium chloride 0.9 mg
benzalkonij klorid 0,025 mg benzalkonium chloride 0.025 mg
dinatrijev edetat 0,05 mg disodium edetate 0.05 mg
pročišćena voda ad 0,1 ml purified water ad 0.1 ml
Postupak priprave Preparation process
Aktivan sastojak i pomoćne tvari se otope u vodi i prenesu u prikladan spremnik. The active ingredient and excipients are dissolved in water and transferred to a suitable container.
Primjer VI Example VI
Injekcijska otopina koji sadrže 5 mg aktivne tvari u 5 ml Injection solution containing 5 mg of active substance in 5 ml
Sastav: Composition:
aktivna tvar 5 mg active substance 5 mg
glukoza 250 mg glucose 250 mg
albumin iz humanog seruma 10 mg albumin from human serum 10 mg
glikofurol 250 mg glycofurol 250 mg
voda za injekcije ad 5 ml water for injections ad 5 ml
Priprava: Preparation:
Glikofurol i glukoza se otope u vodi za injekcije (WfI); doda se albumin iz humanog seruma; aktivni sastojak se otopi uz grijanje; nadopuni se do navedenog volumena s Wfl; prenese se u ampule pod plinom dušikom. Glycofurol and glucose are dissolved in water for injections (WfI); human serum albumin is added; the active ingredient dissolves with heating; make up to the specified volume with Wfl; transfer to ampoules under nitrogen gas.
Primjer VII Example VII
Injekcijska otopina koja sadrži-100 mg aktivne tvari u 20 ml Injection solution containing 100 mg of active substance in 20 ml
Sastav: Composition:
aktivna tvar 100 mg active substance 100 mg
monokalijev dihidrogen fosfat = KH2PO4 12 mg monopotassium dihydrogen phosphate = KH2PO4 12 mg
dinatrijev hidrogen fosfat = Na2HPO4 •2H2O 2 mg disodium hydrogen phosphate = Na2HPO4 •2H2O 2 mg
natrijev klorid 180 mg sodium chloride 180 mg
albumin iz humanog seruma 50 mg albumin from human serum 50 mg
polisorbat 80 20 mg polysorbate 80 20 mg
voda za injekcije ad 20 ml water for injections ad 20 ml
Priprava: Preparation:
Polisorbat 80, natrijev klorid, monokalijev dihidrogen fosfat i dinatrijev hidrogen fosfat se otope u vodi za injekcije (WfI); doda se albumin iz humanog seruma; aktivan sastojak se otopi uz grijanje; nadopuni se na navedeni volumen s WfI; prenese se u ampule. Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate are dissolved in water for injections (WfI); human serum albumin is added; the active ingredient dissolves with heating; it is supplemented to the specified volume with WfI; transferred to ampoules.
Primjer VIII Example VIII
Liofilizat koji sadrži 10 mg aktivne tvari Lyophilisate containing 10 mg of active substance
Sastav: Composition:
aktivna tvar 10 mg active substance 10 mg
manitol 300 mg mannitol 300 mg
albumin iz humanog seruma 20 mg albumin from human serum 20 mg
Priprava: Preparation:
Manitol se otopi u vodi za injekcije (WfI); doda se albumin iz humanog seruma; aktivan sastojak se otopi uz grijanje; nadopuni se na navedeni volumen s WfI; prenese se u vijale; osuši se smrzavanjem. Mannitol dissolves in water for injections (WfI); human serum albumin is added; the active ingredient dissolves with heating; it is supplemented to the specified volume with WfI; transfer to vials; freeze dry.
Otapalo za liofilizat: Solvent for lyophilisate:
polisorbat 80 = Tween 80 20 mg polysorbate 80 = Tween 80 20 mg
manitol 200 mg voda za injekcije ad 10 ml mannitol 200 mg water for injections ad 10 ml
Priprava: Preparation:
Polisorbat 80 i manitol se otope u vodi za injekcije (WfI); prenese se u ampule. Polysorbate 80 and mannitol are dissolved in water for injections (WfI); transferred to ampoules.
Primjer IX Example IX
Tablete koje sadrže 20 mg aktivne tvari Tablets containing 20 mg of active substance
Sastav: Composition:
aktivna tvar 20 mg active substance 20 mg
laktose 120 mg lactose 120 mg
kukuruzni škrob 40 mg corn starch 40 mg
magnezijev stearat 2 mg magnesium stearate 2 mg
Povidon K 25 18 mg Povidone K 25 18 mg
Priprava: Preparation:
Aktivna tvar, laktoza i kukuruzni škrob se homogeno pomiješaju; smjesu se granulira s vodenom otopinom Povidona; umiješa se magnezijev stearat; smjesu se preša u tablete; masa tablete 200 mg. The active substance, lactose and corn starch are mixed homogeneously; the mixture is granulated with an aqueous solution of Povidone; magnesium stearate is mixed in; the mixture is pressed into tablets; tablet mass 200 mg.
Primjer X Example X
Kapsule koje sadrže 20 mg aktivne tvari Capsules containing 20 mg of active substance
Sastav: Composition:
aktivna tvar 20 mg active substance 20 mg
kukuruzni škrob 30 mg corn starch 30 mg
visoko dispergirani silicijev oksid 5 mg highly dispersed silicon oxide 5 mg
magnezijev stearat 2,5 mg magnesium stearate 2.5 mg
Priprava: Preparation:
Aktivna tvar, kukuruzni škrob i silicijev oksid se homogeno pomiješaju; umiješa se magnezijev stearat; smjesu se pakira u tvrde želatinske kapsule veličine 3 pomoću stroja za punjenje kapsula. The active substance, corn starch and silicon oxide are mixed homogeneously; magnesium stearate is mixed in; the mixture is packed into size 3 hard gelatin capsules using a capsule filling machine.
Primjer XI Example XI
Čepići koji sadrže 50 mg aktivne tvari Suppositories containing 50 mg of active substance
Sastav: Composition:
aktivna tvar 50 mg active substance 50 mg
tvrda mastt (Adeps solidus) q.s. ad 1700 mg hard mastt (Adeps solidus) q.s. ad 1700 mg
Priprava: Preparation:
Tvrdu mast- se rastali pri pribi. 38°C; usitnjenu aktivnu tvar se homogeno dispergira u rastaljenoj tvrdoj masti; kad se ohladi na pribl. 35°C prelije se u pothlađene kalupe. Hard fat - they separated during the application. 38°C; the chopped active substance is homogeneously dispersed in melted hard fat; when cooled to approx. 35°C is poured into cooled molds.
Primjer XII Example XII
Injekcijska otopina koja sadrže 10 mg aktivne tvari u 1 ml Injection solution containing 10 mg of active substance in 1 ml
Sastav: Composition:
aktivna tvar 10 mg active substance 10 mg
manitol 50 mg mannitol 50 mg
albumin iz humanog seruma 10 mg albumin from human serum 10 mg
voda za injekcije ad 1 ml water for injections ad 1 ml
Priprava: Preparation:
Manitol se otopi u vodi za injekcije (WfI); doda se albumin iz humanog seruma; aktivan sastojak se otopi uz grijanje; nadopuni se s WfI na navedeni volumen; prenese se u ampule pod plinom dušikom. Mannitol dissolves in water for injections (WfI); human serum albumin is added; the active ingredient dissolves with heating; it is supplemented with WfI to the specified volume; transfer to ampoules under nitrogen gas.
Claims (12)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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DE19952147A DE19952147A1 (en) | 1999-10-29 | 1999-10-29 | New cyclopropanes, pharmaceutical compositions containing these compounds and process for their preparation |
Publications (1)
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HRP20020373A2 true HRP20020373A2 (en) | 2003-10-31 |
Family
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HR20020373A HRP20020373A2 (en) | 1999-10-29 | 2002-04-26 | Novel cyclopropanes as cgrp antagonists, medicaments containing said compounds and method for the production thereof |
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US (2) | US20030139417A1 (en) |
EP (1) | EP1228059B1 (en) |
JP (1) | JP3869721B2 (en) |
KR (1) | KR20020047290A (en) |
CN (1) | CN1177844C (en) |
AT (1) | ATE301117T1 (en) |
AU (1) | AU781856B2 (en) |
BG (1) | BG106638A (en) |
BR (1) | BR0015147A (en) |
CA (1) | CA2387134C (en) |
CZ (1) | CZ20021812A3 (en) |
DE (2) | DE19952147A1 (en) |
EA (1) | EA005137B1 (en) |
EE (1) | EE200200220A (en) |
HK (1) | HK1051858A1 (en) |
HR (1) | HRP20020373A2 (en) |
HU (1) | HUP0203496A3 (en) |
IL (1) | IL148975A0 (en) |
MX (1) | MXPA02004119A (en) |
NO (1) | NO20021799D0 (en) |
NZ (1) | NZ518698A (en) |
PL (1) | PL354715A1 (en) |
SK (1) | SK7282002A3 (en) |
TR (1) | TR200201168T2 (en) |
WO (1) | WO2001032648A1 (en) |
YU (1) | YU30902A (en) |
ZA (1) | ZA200203256B (en) |
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KR20120004541A (en) * | 2002-06-05 | 2012-01-12 | 브리스톨-마이어스 스큅 컴퍼니 | Calcitonin gene related peptide receptor antagonists |
US7220862B2 (en) | 2002-06-05 | 2007-05-22 | Bristol-Myers Squibb Company | Calcitonin gene related peptide receptor antagonists |
US7842808B2 (en) | 2002-06-05 | 2010-11-30 | Bristol-Myers Squibb Company | Anti-migraine spirocycles |
JP2007524568A (en) | 2003-12-05 | 2007-08-30 | ブリストル−マイヤーズ スクイブ カンパニー | Calcitonin gene-related peptide receptor antagonist |
TW200524601A (en) | 2003-12-05 | 2005-08-01 | Bristol Myers Squibb Co | Heterocyclic anti-migraine agents |
TW200533398A (en) | 2004-03-29 | 2005-10-16 | Bristol Myers Squibb Co | Novel therapeutic agents for the treatment of migraine |
ATE537153T1 (en) * | 2004-09-09 | 2011-12-15 | Merck Sharp & Dohme | ARYLSPIROLACTAM COMPOUNDS AS ANTAGONISTS OF THE CGRP RECEPTOR |
US7384931B2 (en) | 2004-11-03 | 2008-06-10 | Bristol-Myers Squibb Company | Constrained compounds as CGRP-receptor antagonists |
US7384930B2 (en) | 2004-11-03 | 2008-06-10 | Bristol-Myers Squibb Company | Constrained compounds as CGRP-receptor antagonists |
US7449586B2 (en) | 2004-12-03 | 2008-11-11 | Bristol-Myers Squibb Company | Processes for the preparation of CGRP-receptor antagonists and intermediates thereof |
US7834007B2 (en) | 2005-08-25 | 2010-11-16 | Bristol-Myers Squibb Company | CGRP antagonists |
EP1954135B1 (en) * | 2005-11-18 | 2012-10-10 | Merck Sharp & Dohme Corp. | Spirolactam aryl cgrp receptor antagonists |
WO2009034029A2 (en) * | 2007-09-07 | 2009-03-19 | Boehringer Ingelheim International Gmbh | 1-substituted 4-heterocyclylpiperidines for use as cgrp antagonists |
BRPI0817835A2 (en) | 2007-10-18 | 2015-03-31 | Boehringer Ingelheim Int | CGRP ANTAGONISTS |
EP2065381A1 (en) | 2007-10-18 | 2009-06-03 | Boehringer Ingelheim Pharma GmbH & Co. KG | CGRP antagonists |
EP2225223B1 (en) | 2007-11-22 | 2017-01-11 | Boehringer Ingelheim International GmbH | Organic compounds |
US9315449B2 (en) | 2008-05-15 | 2016-04-19 | Duke University | Substituted pyrazoles as heat shock transcription factor activators |
UA105182C2 (en) | 2008-07-03 | 2014-04-25 | Ньюрексон, Інк. | Benzoxazines, benzothiazines, and related compounds having nos inhibitory activity |
SG11201406311UA (en) | 2012-04-05 | 2014-11-27 | Chdi Foundation Inc | Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
EP3049389B1 (en) | 2013-09-26 | 2019-08-07 | CHDI Foundation, Inc. | Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
EP3049077A4 (en) | 2013-09-26 | 2017-02-15 | CHDI Foundation, Inc. | Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
JP2019040859A (en) * | 2017-08-22 | 2019-03-14 | 株式会社エンプラス | Light-emitting device, surface light source device and light flux control member |
CN114957145B (en) * | 2022-04-14 | 2023-07-18 | 浙江师范大学 | 1,2,4-benzotriazine derivative and preparation method thereof |
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US3655667A (en) * | 1968-04-04 | 1972-04-11 | Smith Kline French Lab | 1-(2-benzoylcyclopropylmethyl)-4-phenylpiperazines |
US3873707A (en) * | 1972-10-02 | 1975-03-25 | Robins Co Inc A H | 1-Cyclopropyl-3-mono-(and 2,3-di) substituted-1-propanones in compositions and method for treating pain |
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IL124557A0 (en) | 1995-12-15 | 1998-12-06 | Novo Nordisk As | Compositions for reducing blood glucose and/or inhibiting the activity of cgrp |
AU4261697A (en) * | 1996-09-09 | 1998-03-26 | Smithkline Beecham Corporation | Compounds and methods |
BR9712023A (en) | 1996-09-10 | 1999-08-31 | Thomae Gmbh Dr K | Derived amino acids, drugs containing these compounds and processes for their preparation. |
EA003925B1 (en) | 1997-05-22 | 2003-10-30 | Дж.Д.Сирл Энд Ко | SUBSTITUTED PYRAZOLES AS p38 KINASE INHIBITORS |
EP1071679A1 (en) * | 1998-03-17 | 2001-01-31 | Novo Nordisk A/S | Novel heterocyclic compounds |
DE19911039A1 (en) | 1999-03-12 | 2000-09-14 | Boehringer Ingelheim Pharma | Modified amino acid amides, pharmaceutical compositions containing these compounds and process for their preparation |
BR0009338A (en) * | 1999-03-26 | 2001-12-26 | Astrazeneca Ab | Compound, process for preparing it, pharmaceutical composition, process for preparing it, use of a compound, and method of treating an inflammatory disease in a patient suffering or at risk of said disease |
DE19937304C2 (en) | 1999-08-10 | 2003-08-21 | Boehringer Ingelheim Pharma | Use of CGRP antagonists to combat menopausal hot flashes |
US6696418B1 (en) * | 1999-09-01 | 2004-02-24 | Pfizer Inc. | Somatostatin antagonists and agonists that act at the SST subtype 2 receptor |
TWI227231B (en) * | 2000-07-12 | 2005-02-01 | Novartis Ag | 4-benzoyl-piperidine derivatives for treating conditions mediated by CCR-3 |
US6642256B2 (en) * | 2000-12-21 | 2003-11-04 | Warner-Lambert Company Llc | Piperidine derivatives as subtype selective N-Methyl-D-Aspartate antagonists |
WO2003037338A2 (en) * | 2001-11-01 | 2003-05-08 | Vertex Pharmaceuticals Incorporated | Modulators of the cholesterol biosynthetic pathway |
US6977265B2 (en) * | 2001-11-30 | 2005-12-20 | Roche Palo Alto Llc | Piperidine CCR-3 receptor antagonists |
US7026312B2 (en) * | 2002-03-14 | 2006-04-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Substituted piperidines, pharmaceutical compositions containing these compounds, their use and processes for the preparation thereof |
-
1999
- 1999-10-29 DE DE19952147A patent/DE19952147A1/en not_active Withdrawn
-
2000
- 2000-10-21 SK SK728-2002A patent/SK7282002A3/en unknown
- 2000-10-21 AT AT00969529T patent/ATE301117T1/en not_active IP Right Cessation
- 2000-10-21 EP EP00969529A patent/EP1228059B1/en not_active Expired - Lifetime
- 2000-10-21 WO PCT/EP2000/010391 patent/WO2001032648A1/en not_active Application Discontinuation
- 2000-10-21 YU YU30902A patent/YU30902A/en unknown
- 2000-10-21 KR KR1020027005386A patent/KR20020047290A/en not_active Application Discontinuation
- 2000-10-21 BR BR0015147-5A patent/BR0015147A/en not_active Expired - Fee Related
- 2000-10-21 AU AU79213/00A patent/AU781856B2/en not_active Ceased
- 2000-10-21 NZ NZ518698A patent/NZ518698A/en unknown
- 2000-10-21 PL PL00354715A patent/PL354715A1/en not_active Application Discontinuation
- 2000-10-21 DE DE50010886T patent/DE50010886D1/en not_active Expired - Fee Related
- 2000-10-21 CN CNB008151490A patent/CN1177844C/en not_active Expired - Fee Related
- 2000-10-21 MX MXPA02004119A patent/MXPA02004119A/en unknown
- 2000-10-21 CZ CZ20021812A patent/CZ20021812A3/en unknown
- 2000-10-21 IL IL14897500A patent/IL148975A0/en unknown
- 2000-10-21 TR TR2002/01168T patent/TR200201168T2/en unknown
- 2000-10-21 HU HU0203496A patent/HUP0203496A3/en unknown
- 2000-10-21 JP JP2001534799A patent/JP3869721B2/en not_active Expired - Fee Related
- 2000-10-21 CA CA002387134A patent/CA2387134C/en not_active Expired - Fee Related
- 2000-10-21 EE EEP200200220A patent/EE200200220A/en unknown
- 2000-10-21 EA EA200200447A patent/EA005137B1/en not_active IP Right Cessation
-
2002
- 2002-04-12 US US10/121,872 patent/US20030139417A1/en not_active Abandoned
- 2002-04-17 NO NO20021799A patent/NO20021799D0/en not_active Application Discontinuation
- 2002-04-23 BG BG106638A patent/BG106638A/en active Pending
- 2002-04-24 ZA ZA200203256A patent/ZA200203256B/en unknown
- 2002-04-26 HR HR20020373A patent/HRP20020373A2/en not_active Application Discontinuation
-
2003
- 2003-06-11 HK HK03104096A patent/HK1051858A1/en not_active IP Right Cessation
-
2005
- 2005-06-27 US US11/169,078 patent/US7407963B2/en not_active Expired - Lifetime
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